InteractiveFly: GeneBrief

Tao: Biological Overview | References


Gene name - Tao

Synonyms - tao-1

Cytological map position - 18D2-18D3

Function - signal transduction

Keywords - Hippo pathway, restriction of cell proliferation in imaginal discs, control of epithelial morphogenesis by promoting Fasciclin 2 endocytosis, maternal, negative regulator of microtubule plus-end growth, regulates Skl expression in pole cells, regulation of apoptosis

Symbol - Tao

FlyBase ID: FBgn0031030

Genetic map position - chrX:19,463,995-19,473,925

Classification - PKc_like: Protein Kinases, catalytic domain

Cellular location - cytoplasmic



NCBI links: Precomputed BLAST | EntrezGene

Recent literature
Chung, H. L., Augustine, G. J. and Choi, K. W. (2016). Drosophila Schip1 links Expanded and Tao-1 to regulate Hippo signaling. Dev Cell 36: 511-524. PubMed ID: 26954546
Summary:
Regulation of organ size is essential in animal development, and Hippo (Hpo) signaling is a major conserved mechanism for controlling organ growth. In Drosophila, Hpo and Warts kinases are core components of this pathway and function as tumor suppressors by inhibiting Yorkie (Yki). Expanded (Ex) is a regulator of the Hpo activity, but how they are linked is unknown. This study shows that Schip1, a Drosophila homolog of the mammalian Schwannomin interacting protein 1 (SCHIP1), provides a link between Ex and Hpo. Ex is required for apical localization of Schip1 in imaginal discs. Schip1 is necessary for promoting membrane localization and phosphorylation of Hpo by recruiting the Hpo kinase Tao-1. Taking these findings together, it is concluded that Schip1 directly links Ex to Hpo signaling by recruiting Tao-1. This study provides insights into the mechanism of Tao-1 regulation and a potential growth control function for SCHIP1 in mammals.

BIOLOGICAL OVERVIEW

Recent studies have shown that the Hippo-Salvador-Warts (HSW) pathway restrains tissue growth by phosphorylating and inactivating the oncoprotein Yorkie. How growth-suppressive signals are transduced upstream of Hippo remains unclear. This study shows that the Sterile 20 family kinase, Tao-1, directly phosphorylates T195 in the Hippo activation loop and that, like other HSW pathway genes, Tao-1 functions to restrict cell proliferation in developing imaginal epithelia. This relationship appears to be evolutionarily conserved, because mammalian Tao-1 similarly affects MST kinases. In S2 cells, Tao-1 mediates the effects of the upstream HSW components Merlin and Expanded, consistent with the idea that Tao-1 functions in tissues to regulate Hippo phosphorylation. These results demonstrate that one family of Ste20 kinases can activate another and identify Tao-1 as a component of the regulatory network controlling HSW pathway signaling, and therefore tissue growth, during development (Boggiano, 2011).

During development, organisms must determine the overall size and shape of their individual organs through mechanisms not fully understood. The recent discovery of the evolutionarily conserved Hippo-Salvador-Warts (HSW) signaling pathway has revealed a unique mechanism to regulate proliferation independent of developmental patterning. The core members of the HSW pathway, Hippo (Hpo) and Warts (Wts), together with their scaffolding partners Salvador (Sav) and Mats, phosphorylate and inactivate the transcriptional co-activator Yorkie (Yki). Phosphorylation prevents Yorkie from translocating to the nucleus where it binds to TEAD-family transcription factors and drives the transcription of genes that promote growth and inhibit apoptosis. Loss of HSW pathway function in Drosophila leads to increased cellular proliferation resulting in tumor-like overgrowths in epithelial tissues. Similarly, knockout mouse models of HSW homologs grow tumors, and human HSW homologs have been implicated in cancers. These studies suggest that HSW signaling is a crucial part of an organism's ability to regulate cell proliferation and overall tissue size (Boggiano, 2011 and references therein).

A central, unanswered question regarding HSW function is how the activity of Hpo, the most upstream kinase in the pathway is regulated. The atypical cadherin Fat and its ligand Dachsous can function at the plasma membrane to initiate HSW signaling, however the extracellular cues that trigger signaling and the mechanism by which Fat activates Hpo remain elusive. In addition, genetic evidence strongly suggests that another source of Hpo activation functioning in parallel to Dachsous-Fat activation must exist. At least three different cytoplasmic proteins are believed to act upstream of Hpo to initiate signaling through the pathway, Expanded (Ex), Merlin (Mer), and Kibra. Ex and Mer are members of the Four-point-one, Ezrin, Radixin, Moesin (FERM) family and Kibra is a WW-domain containing protein. Though these three proteins are thought to physically interact with each other in varying complexes, only Ex can form a complex with Hpo (Yu, 2010) and it is unclear how this interaction leads to activation of Hpo. Moreover, there is strong genetic evidence that Ex, Mer, and Kibra act in parallel to each other, implying that other mechanisms for activating Hpo independently of Ex must exist (Boggiano, 2011).

This study sought to identify genes that might function upstream of Hpo to activate the pathway using a candidate gene approach and discovered that the Sterile 20 kinase Tao-1 is a member of this signaling pathway. Tao-1 previously has been shown to destabilize microtubules and has been implicated in apoptosis in the Drosophila germline (Sato, 2007; Liu, 2010). This study shows that loss of Tao-1 function results in increased cellular proliferation and upregulation of Yki target gene expression. It was further demonstrated that Tao-1 regulates HSW pathway activity by phosphorylating Hpo at a critical activating residue. Thus, these results identify Tao-1 as a member of the HSW pathway and provide a molecular mechanism for Hpo activation (Boggiano, 2011).

In an effort to identify additional regulators of HSW signaling, this study examined the role of Tao-1 in growth control during development. Tao-1 depletion in either the eye or wing epithelium results in overgrowth phenotypes as well as transcriptional upregulation of HSW targets. Using a combination of genetic epistasis, experiments in cultured S2 cells, and in vitro biochemistry, it was demonstrated that Tao-1 directly phosphorylates the critical T195 regulatory residue in the activation loop of Hpo to promote HSW pathway activation. The observation that a mammalian orthologue of Tao-1, TAOK3, can phosphorylate MST kinases at the same residue further suggests that this regulatory function is conserved in mammals. Taken together, these results implicate Tao-1 as a component of HSW signaling (see A model for Tao-1's function in the HSW pathway) and reveal a mechanism for regulation of Hpo activity (Boggiano, 2011).

While Tao-1 depletion results in overgrowth phenotypes that are similar to mutations in other HSW pathway genes, these phenotypes are less severe than those of core components such as hpo and wts. One likely explanation for this is that the RNAi transgenes that were used in these studies do not completely remove Tao-1 function. It is also possible that there are multiple mechanisms for activating HSW signaling, including, but not limited to, Tao-1 phosphorylation of Hpo. Indeed, previous studies have demonstrated that the upstream components Mer, Ex, and Kibra act, at least in part, in parallel to activate Hpo. Biochemical evidence indicates that two of these proteins, Mer and Ex, function with Tao-1 to activate HSW signaling. While it is probable that Kibra functions upstream of Tao-1, it cannot be ruled out that Kibra functions independently of Mer and Ex to activate HSW signaling in a Tao-1-independent manner. Further genetic analysis using a Tao-1 null allele would be helpful in defining Tao-1's role relative to other HSW components, but unfortunately the deletions associated with the sole existing Tao-1 null allele, Tao-150, also appear to affect an adjacent gene. In addition, Tao-1 maps very close to the most proximal FRT element on the X chromosome, making it difficult to generate recombinant chromosomes for somatic mosaic analysis (Boggiano, 2011).

How do Mer, Ex and Tao-1 cooperate to regulate Hpo phosphorylation? Given that Ex has been shown to interact with Hpo (Yu, 2010), one possibility is that Mer and Ex function to scaffold Tao-1 together with Hpo, thereby promoting the ability of Tao-1 to phosphorylate and activate Hpo. However, despite repeated attempts it has not been possible to detect Tao-1 in a complex with either Mer or Ex, and knockdown of Mer, ex or kibra does not diminish the ability of Tao-1 to promote Hpo phosphorylation in S2 cells. For these reasons, the possibility is favored that Mer and Ex indirectly affect Tao-1 function, perhaps by interacting with other proteins that in turn directly regulate Tao-1. For example, Tao-1 activity could be directly regulated by an unknown receptor at the cell surface whose localization or activity is controlled by interaction with Mer and Ex. This notion is consistent with the fact that both Mer and Ex have FERM domains, which are known to interact with the cytoplasmic tails of transmembrane proteins. Previous studies have suggested that Ex interacts with the transmembrane protein Crumbs, though the mechanistic significance of this interaction is unclear. It is not currently known whether Drosophila Merlin has transmembrane binding partners (Boggiano, 2011).

Two additional ideas related to Tao-1 function are suggested by the current data. In S2 cells, Tao-1 kinase activity is required for normal levels of Hpo phosphorylation at T195 in the kinase activation loop, suggesting that Tao-1 could function to maintain constant, low levels of pathway activation. In turn, this low level of Hpo activation might be necessary so that other, regulated inputs into HSW activity can quickly transition cells away from actively dividing and into a differentiated state following periods of growth. Alternatively, it is possible that Tao-1 activity itself is dynamically regulated during development, allowing it to rapidly alter levels of HSW pathway activity via its effect on Hpo phosphorylation. In either case, phosphorylation by Tao-1 at T195 is likely to promote Hpo's known ability to undergo autophosphorylation, thus amplifying the effect of even a small change in Tao-1 activity. Further studies will be required to answer these questions and to determine if, and how, Tao-1 activity is regulated (Boggiano, 2011).

An interesting aspect of the discovery that Tao-1 regulates HSW signaling is that Tao-1, and its mammalian orthologues TAOK1-3, have been shown to regulate MT stability (Mitsopoulos, 2003; Timm, 2003; Liu, 2010). The current results indicate that this effect on MT stability is not mediated through HSW signaling, since mutations in other HSW pathway components do not display similar MT phenotypes. However, it is interesting to speculate that Tao-1's association with MTs might affect its ability to regulate HSW pathway activation. More work will be required to determine whether the function of Drosophila Tao-1 in HSW signaling is entirely independent of its role in microtubule dynamics, though a recent study in mammalian cultured cells found that microtubule disruption did not affect localization of Yap, a mammalian Yki ortholog, suggesting that in mammalian cells these roles might be independent (Boggiano, 2011).

An additional possible mechanistic link between Tao-1 and HSW signaling is suggested by studies in flies and in mammalian cells indicating that Par-1, a polarity protein, is positively regulated by Tao-1 (Timm, 2003; King, 2011). Par-1 has been shown to promote basolateral polarity in the Drosophila follicular epithelium and to regulate the stability and organization of MTs in these cells. Recent studies have implicated components of both apical and basolateral polarity in the regulation of HSW signaling (reviewed in Halder, 2011). Conversely, HSW signaling also seems to feed back onto Crumbs, an apical determinant, and perhaps other components to regulate apical-basal polarity. Whether Tao-1 plays a role in the linkage between cell polarity and growth control remains to be established, but the ability to both directly activate Hpo function through phosphorylation and control cytoskeletal organization and cell polarity through microtubule organization potentially places Tao-1 in a unique position to coordinate these important cellular processes (Boggiano, 2011).

The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway

The Salvador-Warts-Hippo (SWH) pathway is a complex signaling network that controls both developmental and regenerative tissue growth. Using a genetic screen in Drosophila melanogaster, the sterile 20-like kinase, Tao-1, was identified as an SWH pathway member. Tao-1 controls various biological phenomena, including microtubule dynamics, animal behavior, and brain development. This study describes a role for Tao-1 as a regulator of epithelial tissue growth that modulates activity of the core SWH pathway kinase cassette. Tao-1 functions together with Hippo to activate Warts-mediated repression of Yorkie. Tao-1's ability to control SWH pathway activity is evolutionarily conserved because human TAO1 can suppress activity of the Yorkie ortholog, YAP. Human TAO1 controls SWH pathway activity by phosphorylating, and activating, the Hippo ortholog, MST2. Given that SWH pathway activity is subverted in many human cancers, these findings identify human TAO kinases as potential tumor suppressor genes (Poon, 2011).

Genetic and biochemical studies have pointed to the existence of unidentified SWH pathway kinases. Among known SWH pathway kinases, Wts phosphorylates and represses Yki, whereas Hpo activates Wts by phosphorylating the other core kinase cassette proteins, Wts, Sav, and Mats. Proteins that activate Hpo are less well defined. Using a Drosophila genetic screen, this study has identified the sterile 20-like kinase Tao-1 as a SWH pathway protein. By modulating Tao-1 expression, a role was uncovered for this kinase as a suppressor of epithelial tissue growth during Drosophila development. Several points of evidence have led to the proposal that Tao-1 regulates tissue growth by activating the core SWH pathway kinase cassette: (1) tissue with reduced Tao-1 activity displayed several phenotypic similarities to tissue mutant for members of the core SWH pathway kinase cassette, including Yki hyperactivation; (2) alterations in tissue size caused by altered SWH pathway activity were modifiable by Tao-1 hemizygosity; and (3) Tao-1 overexpression activated the core SWH pathway kinase cassette (Poon, 2011).

The observation that Tao-1 is necessary for Hpo overexpression to suppress tissue growth suggests that either Hpo functions either upstream of Tao-1 or, alternatively, that Tao-1 was required to activate Hpo, even when Hpo is overexpressed. The latter scenario is favored based on several biochemical results: (1) Tao-1 overexpression requires Hpo to stimulate Wts activity in Drosophila S2 cells, but the inverse relationship was not observed; (2) human TAO1 stimulates phosphorylation of the Hpo ortholog, MST2, in in vitro kinase assays; and (3) TAO1 activates MST2 in human cultured cells. This model is also in keeping with biochemical studies that showed that Hpo/MST1/2 activate Wts/LATS1/2 by phosphorylating these proteins directly, rather than via an intermediary kinase(Poon, 2011).

Tao-1's role as a SWH pathway kinase appears to be conserved throughout evolution because one of its three human homologs, TAO1, represses YAP activity in a manner that is reliant on the SWH pathway core kinase cassette and because TAO1 was found to phosphorylate and activate MST2. This is the first described example of a sterile 20-like kinase family member phosphorylating another kinase from this family. To help address the mechanism by which TAO1 regulates MST2, it will be important to define the MST2 residue(s) that TAO1 phosphorylates (Poon, 2011).

Currently, it is unclear whether Tao-1's ability to control the SWH pathway is regulated or whether it is constitutively active. Several upstream regulatory branches of the SWH pathway have been identified in recent years and appear to regulate the SWH pathway largely by impinging on the core kinase cassette. Ft promotes Wts stability, whereas both Ft and Crb regulate the levels and apical junctional localization of Ex. Lgl and aPKC have been proposed to influence SWH pathway activity by regulating the subcellular localization of Hpo and dRASSF. Kibra, Ex, and Mer can interact with members of the core kinase cassette, recruit Hpo to the plasma membrane, and induce activation of Hpo and Wts. Given that no evidence of physical interactions was found between Tao-1 and several upstream SWH pathway proteins (e.g., Kibra, Ex, and Mer), biochemical studies aimed at identifying Tao-1-interacting proteins are likely to shed light on the question of Tao-1 regulation(Poon, 2011).

Interestingly, Tao-1 has been shown to regulate microtubule polymerization at the cell cortex in both Drosophila and mammalian cells (Liu, 2010; Timm, 2003). At present there is no evidence to suggest that Tao-1's abilities to regulate SWH pathway-dependent tissue growth and microtubule stability are in any way linked. However, it is interesting to note that mechanical tension has been shown to regulate microtubule polymerization at the cell cortex, and has been hypothesized to regulate tissue growth and the SWH pathway. Therefore, it is tempting to speculate that Tao-1/TAO1 kinases could act as a point of convergence between mechanical tension, the SWH pathway, and control of tissue growth (Poon, 2011).

This study has shown that Tao-1's SWH pathway regulatory function is conserved in mammalian cells. It will be important to extend these findings to determine whether the TAO1, 2, and 3 kinases control the growth of mammalian tissues. In addition, given that SWH pathway activity is subverted at a high frequency in many human tumor types, it raises the possibility that TAO1, 2, and 3 function as tumor suppressor genes. According to the COSMIC and Tumorscape databases, TAO1, 2, and 3 do not appear to be mutated or deleted at a high frequency in the tumors that were surveyed. However, based on the current finding that Tao-1 controls SWH pathway-dependent tissue growth, a closer examination of the potential tumor suppressor function of human TAO kinases is warranted, particularly in cancers that are known to exhibit enhanced YAP activity (Poon, 2011).

The sterile 20-like kinase tao controls tissue homeostasis by regulating the hippo pathway in Drosophila adult midgut

The proliferation and differentiation of adult stem cells must be tightly controlled in order to maintain resident tissue homeostasis. Dysfunction of stem cells is implicated in many human diseases, including cancer. However, the regulation of stem cell proliferation and differentiation is not fully understood. This study shows that the sterile-like 20 kinase, Tao, controls tissue homeostasis by regulating the Hippo pathway in the Drosophila adult midgut. Depletion of Tao in the progenitors leads to rapid intestinal stem cell (ISC) proliferation and midgut homeostasis loss. Meanwhile, it was find that the STAT signaling activity and cytokine production are significantly increased, resulting in stimulated ISC proliferation. Furthermore, expression of the Hippo pathway downstream targets, Diap1 and bantam, is dramatically increased in Tao knockdown intestines. Consistently, it was shown that the Yorkie (Yki) acts downstream of Tao to regulate ISC proliferation. Together, these results provide insights into understanding of the mechanisms of stem cell proliferation and tissue homeostasis control (Huang, 2014).

Tao controls epithelial morphogenesis by promoting Fasciclin 2 endocytosis

Regulation of epithelial cell shape, for example, changes in relative sizes of apical, basal, and lateral membranes, is a key mechanism driving morphogenesis. However, it is unclear how epithelial cells control the size of their membranes. In the epithelium of the Drosophila melanogaster ovary, cuboidal precursor cells transform into a squamous epithelium through a process that involves lateral membrane shortening coupled to apical membrane extension. This paper reports a mutation in the gene Tao, which resulted in the loss of this cuboidal to squamous transition. The inability of Tao mutant cells to shorten their membranes was caused by the accumulation of the cell adhesion molecule Fasciclin 2, the Drosophila N-CAM (neural cell adhesion molecule) homologue. Fasciclin 2 accumulation at the lateral membrane of Tao mutant cells prevented membrane shrinking and thereby inhibited morphogenesis. In wild-type cells, Tao initiated morphogenesis by promoting Fasciclin 2 endocytosis at the lateral membrane. Thus, this study identified a mechanism controlling the morphogenesis of a squamous epithelium (Gomez, 2012).

This study reports a novel mechanism regulating the morphogenesis of a squamous epithelium. The data show that timely controlled removal of the adhesion molecule Fas2 from the lateral membrane is critical for the stretching of cuboidal precursor cells. In this process, Tao initiates morphogenesis by promoting Fas2 endocytosis from the lateral membrane, which reduces adhesive forces and thereby provides plasticity for the cuboidal to squamous cell shape change. The results are consistent with a model in which homophilic Fas2 interactions act as a glue preventing shortening of the membrane (Gomez, 2012).

Tao function is essential for the process of stretching of epithelial cells. However, the data indicate that Tao uses none of its known pathways to control morphogenesis. Similarly, no evidence was found that Tao regulates cell stretching via the cytoskeleton. Moreover, the results argue against a role for Tao in transcriptional repression of Fas2, indicating a function in posttranslational regulation. Indeed, quantitative analysis of Fas2 vesicles in wild-type follicles indicates that membrane shrinking is initiated by enhanced endocytosis. Tao mutant cells have a reduced ability to internalize Fas2 vesicles, contain tubular Fas2 structures typical for endocytosis defects, and show fewer endocytotic Fas2 vesicles in the cytoplasm. This indicates that the overaccumulation of Fas2 at the lateral membrane is caused by defective Fas2 internalization, suggesting a role for Tao in promoting endocytosis at the lateral membrane. A similar function of Tao in triggering endocytosis of homophilic adhesion proteins has been identified in cultured hippocampal neurons (Yasuda, 2007). In contrast to the follicular epithelium, however, Tao is acting via the p38 MAP signaling pathway in this cell type (Gomez, 2012).

Tao promotes Fas2 endocytosis not only in the anterior squamous epithelium but acts also in the posterior epithelium, whose cells become columnar by elongating their lateral membrane. Although it is surprising that these cells down-regulate a protein that is able to induce cell elongation, it appears that during stage 7/8, all epithelial cells clear their lateral membrane from Fas2 to allow morphogenesis. This suggests that other proteins than Fas2 are responsible for cell elongation in the posterior epithelium (Gomez, 2012).

Is Tao an endocytosis promoter specific for the lateral membrane? Endocytosis is only impaired but not blocked in Tao mutant cells, as they are still able to internalize reduced levels of dextran and Fas2. Consistent with this, the Tao phenotype differs from mutants affecting endocytosis in general. Although cell clones mutant for Rab5, the syntaxin family member Avalanche, and Dynamin/Shibire show severe polarity defects and massive overproliferation in the follicular epithelium, the Tao phenotype is restricted to overaccumulation of membrane proteins and cell shape defects. It is therefore concluded that Tao is not a general endocytosis factor but enhances endocytosis at a critical developmental stage to allow epithelial morphogenesis (Gomez, 2012).

This timely controlled requirement of Tao function raises the question whether Tao expression starts just before the onset of morphogenesis or whether the protein is present also in early stages and only activated when Fas2 has to be removed from the lateral membrane. Endogenous Tao protein could not be detected, as antibodies showed no specific signal in the follicular epithelium. Moreover, analysis of Tao mRNA expression does not allow unambiguous conclusions about the onset of Tao transcription in the follicular epithelium as a strong signal from the germline cyst covers the signal in the surrounding epithelium (Gomez, 2012).

Using a HA fusion protein, Tao protein was detected at the lateral membrane and in the basolateral cytoplasm of the follicular epithelium. Interestingly, Tao protein accumulation appears as a gradient with the lowest levels in the apical and the highest levels in the basal region of the follicular epithelium. Since rescue experiments demonstrate the functionality of the fusion protein, a gradient of endogenous Tao activity might also exist. This raises the possibility that Tao promotes endocytosis more strongly in basal regions of the lateral membrane. It is speculated that there is a switch in Tao activity at the border between the lateral and the basal membrane and that the basal membrane domain is protected from Tao function. A spatial restriction of Tao function to the lateral membrane could be achieved by the localization of a yet unidentified target of Tao kinase. Such a Tao mediator could exclusively localize to the lateral membrane (Gomez, 2012).

The finding that not only Fas2 but also apical and apicolateral proteins, such as DE-cadherin and Crb, overaccumulate in Tao mutants might argue against a restriction of Tao function to the lateral membrane. However, in the light of the dramatic change in the geometry of stretching cells, an alternative explanation for the accumulation of these proteins seems more likely. Squamous cell morphogenesis involves a 15-fold surface expansion, which is accompanied by a strong increase in the amounts of proteins determining the apical membrane and forming the adherens junctions. Interestingly, also, posterior cells expand their surface, albeit in less dramatic manner. Tao mutant cells are unable to increase their surface area, but they nevertheless produce the same amount of apical and apicolateral proteins, which then concentrate within a restricted area. It is therefore proposed that the accumulation of Arm, DE-cadherin, and apical proteins in Tao mutant cells is not caused by impaired endocytosis but a result of the inability of these cells to increase their surface area. Consistent with this, it was found that cells whose stretching is prevented by Fas2 overexpression (and which are wild type for Tao function) also concentrate Arm within their restricted apical surface (Gomez, 2012).

A membrane domain-specific endocytosis function for Tao is also supported by experiments, which deplete Fas2 in Tao mutant cells. If Tao would act all along the plasma membrane, Fas2 removal from the lateral membrane should selectively rescue the lateral defect (i.e., Fas2 accumulation) but should not suppress the accumulation of apical and apicolateral proteins (e.g., Arm). However, Fas2 Tao double mutant cells do suppress Arm accumulation. Thus, the primary defect of Tao mutants is Fas2 accumulation, which prevents stretching and expansion of the apical surface. The concentration of Arm is only a secondary effect of the cell shape defect. In conclusion, the data favor a model in which Tao promotes endocytosis specifically at the lateral membrane to relieve Fas2-mediated cell adhesion (Gomez, 2012).

The identification of a mechanism initiating epithelial morphogenesis in the follicular epithelium allows the current model of squamous cell morphogenesis in the follicular epithelium to be updaed. Before morphogenesis, all epithelial cells are cuboidal and adhere apicolaterally via DE-cadherin and more basolaterally via Fas2 interactions. In this period, Fas2 is endocytosed and recycled back to the membrane. Morphogenesis is primed by the Tao kinase, which promotes the endocytosis of Fas2 vesicles. It is assumed that a large proportion of the Fas2 vesicles enter the lysosomal pathway, leading to Fas2 degradation. The removal of Fas2 from the lateral membrane is a critical first step, which allows morphogenesis to occur. Once Fas2 has disappeared, the cuboidal shape of the epithelial cells is solely stabilized by the zonula adherens. Cell flattening requires a tensile force, and morphometric analysis indicates that this force originates from the continuously growing germline cyst, which stretches cells in the anterior epithelium. Flattening correlates well with the local breakdown of the zonula adherens, suggesting an important role for adherens junctions remodeling in cell stretchin. Although the exact molecular mechanism controlling remodeling has still to be elucidated, the data indicate that before cell stretching, lateral cell adhesion has to be reduced to provide morphogenetic plasticity to the lateral membrane (Gomez, 2012).

Given the critical role of Fas2 down-regulation for epithelial stretching, it is counterintuitive that Fas2 mutant cells undergo normal morphogenesis. However, a similar scenario has been shown for the morphogenesis of the peripheral nervous system (PNS) in Drosophila. Here, Fas2 has to be endocytosed in axons to allow glia cell migration. Despite this important function for Fas2 down-regulation, Fas2 mutants show no gross morphological defects in the PNS. Thus, although Fas2 down-regulation is critical for epithelial and PNS morphogenesis, both tissues can compensate for the complete loss of the protein. It is proposed that Fas2 helps to stabilize a morphological state and allows development to proceed only after its timely controlled endocytosis. This mechanism guarantees the correct timing of morphogenesis and thereby helps to coordinate the development of different cell types and tissues. In the follicular epithelium, Fas2 might collaborate with the zonula adherens in counteracting the pressure from the growing germline cyst. As a result, the cuboidal cell shape is stabilized and premature, and uncontrolled stretching is prevented. Subsequently, Fas2 internalization overcomes this control mechanism, and epithelial morphogenesis proceeds (Gomez, 2012).

Tao-1 is a negative regulator of microtubule plus-end growth

Microtubule dynamics are dominated by events at microtubule plus ends as they switch between discrete phases of growth and shrinkage. Through their ability to generate force and direct polar cell transport, microtubules help to organise global cell shape and polarity. Conversely, because plus-end binding proteins render the dynamic instability of individual microtubules sensitive to the local intracellular environment, cyto-architecture also affects the overall distribution of microtubules. Despite the importance of plus-end regulation for understanding microtubule cytoskeletal organisation and dynamics, little is known about the signalling mechanisms that trigger changes in their behaviour in space and time. This study identified a microtubule-associated kinase, Drosophila Tao-1, as an important regulator of microtubule stability, plus-end dynamics and cell shape. Active Tao-1 kinase leads to the destabilisation of microtubules. Conversely, when Tao-1 function is compromised, rates of cortical-induced microtubule catastrophe are reduced and microtubules contacting the actin cortex continue to elongate, leading to the formation of long microtubule-based protrusions. These data reveal a role for Tao-1 in controlling the dynamic interplay between microtubule plus ends and the actin cortex in the regulation of cell form (Liu, 2010).

This paper shows that a conserved microtubule-associated kinase, Tao-1, regulates microtubule dynamics and is required to limit the growth of microtubule plus ends as they contact the actin-based cell cortex. The idea that Tao-1 acts on microtubules confirms the conclusions of previous work on the mammalian homologues of Tao-1. It should be noted however that one of its human homologues, Tao kinase 2, is reported to stabilise microtubules (Mitsopoulos, 2003), implying that the different homologues might have taken on divergent functions in human cells (Liu, 2010).

Interestingly, in Drosophila cells in culture, the phenotypic effect of Tao-1 silencing mirrors the effects of a loss of lamellipodial actin, as seen for example following SCAR/WAVE RNAi. In this case, the actin cortex is weakened, allowing normally growing microtubules to generate microtubule-based protrusions as they polymerise and push on the plasma membrane. By contrast, the spiky Tao-1 RNAi phenotype appears to develop in stages. First, cells appear to have a macroscopically normal actin cytoskeleton. The cell edge then becomes gradually distorted over time as a result of the unchecked growth of microtubules that fail to undergo catastrophe when reaching the cortex. Although an additional role for Tao-1 in the regulation of actin filaments in this process cannot be completely rule out, as previously proposed (Johne, 2008), this analysis suggests that Tao-1 acts primarily on the microtubule cytoskeleton. The change in microtubule dynamics then alters the balance of forces acting to determine S2R+ cell shape, as the mechanically strong actin-rich cortex resists the protrusive forces generated by microtubule plus-end growth. A similar finely tuned balance has been proposed to underlie interactions between the actin cytoskeleton and microtubules in the regulation of axonal extension. Moreover, mechanical force has been shown to contribute directly to microtubule catastrophes and has been proposed to have a significant role in guiding microtubule organisation in yeast. Force could therefore have a significant role in the Tao-1-dependent regulation of microtubule dynamics (Liu, 2010).

The ability of Tao-1 to regulate interactions between microtubule plus ends and the cell cortex could be mediated by a variety of molecular mechanisms. Because endogenous Tao-1 localises both to microtubules and at the cortex, as suggested by studies of the mammalian Tao-1 homologues (Johne, 2008; Mitsopoulos, 2003; Zihni, 2007), the kinase could act to bridge the interface between microtubules and actin filaments, as previously proposed for other microtubule-binding proteins such as ACF7/Kakapo/Shot. In this context, it is noted that some algorithms identify a region within Tao-1 with homology to Smc proteins within its central regulatory domain, which was recently proposed to function as an actin-dependent ATPase in the context of ACF7. In addition, the human Tao-1 homologue was recently reported to modulate the activity of Spred1 and TESK1 to affect actin-microtubule interactions (Johne, 2008). The role of Tao-1 in the ability of microtubules to sense and respond to these cortical forces is also reminiscent of the recent report that Drosophila Shot (a hit in screen reported in this study) acts in concert with cortical F-actin to check the growth of microtubules in neuronal growth cones, suggesting that Tao-1 is part of a hitherto unappreciated class of proteins that can execute this important function of linking the two major cytoskeletal systems (Liu, 2010).

A detailed biochemical analysis will be required to reveal the molecules phosphorylated by Tao-1 to negatively regulate microtubule stability and dynamics. Nevertheless, the current analysis shows that the kinase and C-terminal coiled-coil domains are required for this activity. Based on these findings, Tao-1 could function by phosphorylating one or more of the proteins on the plus ends of microtubules to mediate its effect on microtubule dynamics, as has been proposed for GSK-3. In light of this, the preliminary results showing that EB1 and Tao-1 genetically interact are intriguing, but further experiments will be required to dissect the effect of Tao-1 activity on the plus-end complex (Liu, 2010).

In conclusion, this study identifies the Tao-1 kinase as an important component of the machinery required to make microtubule plus-end growth sensitive to local environmental cues. Significantly, this ability of Tao-1 to regulate the dialogue between the actin cortex and microtubules appears to be crucial for the ability of the actin-based cell cortex to alter microtubule dynamics, and hence for proper regulation of cell shape (Liu, 2010).

Par-1 regulates tissue growth by influencing hippo phosphorylation status and hippo-salvador association

The evolutionarily conserved Hippo (Hpo) signaling pathway plays a pivotal role in organ size control by balancing cell proliferation and cell death. This study reports the identification of Par-1 as a regulator of the Hpo signaling pathway using a gain-of-function EP screen in Drosophila melanogaster. Overexpression of Par-1 elevates Yorkie activity, resulting in increased Hpo target gene expression and tissue overgrowth, while loss of Par-1 diminishes Hpo target gene expression and reduces organ size. par-1 functions downstream of fat and expanded and upstream of hpo and salvador (sav). In addition, it was also found that Par-1 physically interacts with Hpo and Sav and regulates the phosphorylation of Hpo at Ser30 to restrict its activity. Par-1 also inhibits the association of Hpo and Sav, resulting in Sav dephosphorylation and destabilization. Furthermore, evidence is provided that Par-1-induced Hpo regulation is conserved in mammalian cells. Taken together, these findings identified Par-1 as a novel component of the Hpo signaling network (Huang, 2013).

The Hpo signaling pathway has emerged as a conserved pathway that controls tissue growth and balances tissue homeostasis via the regulation of the downstream Sd-Yki transcription complex. Despite the importance of this pathway in development and carcinogenesis, many unknown regulators of the Hpo pathway remain to be identified. This study identified Par-1 as one such Hpo pathway regulator via a genetic overexpression screen using Drosophila EP lines. This study demonstrated that Par-1 was essential for the restriction of Hpo signaling. It was also demonstrated that overexpression of Par-1 promotes tissue growth via the inhibition of the Hpo pathway, whereas loss of Par-1 promotes Hpo signaling to suppress growth and induce apoptosis. Using the Drosophila eye and wing imaginal discs as well as cultured cells, this study provides the first genetic and biochemical evidence for a function of Par-1 in the Hpo pathway (Huang, 2013).

Although the conserved function of Hpo has been well studied, the regulatory mechanism of its kinase activity is still largely obscure. Currently, the regulatory mechanism of Hpo kinase activity is believed to mainly be dependent on autophosphorylation by altering the phosphorylation status of the Thr195. However, whether the uncharacterized phosphorylation events of Hpo, which have been identified in several recent proteome-wide phosphorylation studies, contribute to the regulation of Hpo activity is still unknown. By studying the mechanism underlying Par-1 function in Hpo signaling, this study demonstrated that Par-1 induces Hpo phosphorylation at Ser30 and this leads to the regulation of Hpo kinase activity (Huang, 2013).

In recent proteome-wide phosphorylation studies using Drosophila embryos, it was suggested that Hpo was phosphorylated at Ser30 in vivo, indicating an important role for the Ser30 site in the regulation of Hpo activity. To determine the biological significance of Hpo phosphorylation at Ser30 induced by Par-1, whether Ser30 phosphorylation state affects Hpo phosphorylation at Thr195, which is important for Hpo activation, was tested. Par-1, but not Par-1-KD, was shown to significantly inhibit Hpo phosphorylation levels at Thr195, whereas this inhibitory effect was abolished when the Ser30 site was mutated. More importantly, phosphorylation at Thr195 was slightly elevated when Ser30 was mutated into an alanine. These findings suggested that Par-1 regulates Hpo activity via antagonizing phosphorylation at the Thr195 site by regulating Ser30 phosphorylation. It has been reported that the Hpo Thr195 site is not only auto-phosphorylated but also phosphorylated by Tao-1 (Boggiano, 2011; Poon, 2011), a partner of Par-1 in the regulation of microtubule dynamics. Thus, it was asked whether Par-1-induced phosphorylation at Ser30 also affects Tao-1-mediated phosphorylation at Thr195. Par-1 was shown to suppress Tao-1-mediated phosphorylation at Thr195. The antagonistic effect of Par-1 and Tao-1 on Hpo phosphorylation at Thr195 motivated the examination of the interrelationship of Par-1 and Tao-1 in the Hpo pathway. It was found that Tao-1 disrupted Par-1-induced phosphorylation mobility shift of Hpo-KD, suggesting that the function of Par-1 in the Hpo pathway was modulated by upstream signaling (Huang, 2013).

Several unresolved questions remain. The interaction between Par-1 and Hpo/Sav may be tightly regulated because full-length Par-1 only weakly interacts with Hpo/Sav, unlike the interaction with the N-terminal fragment of Par-1. However, the triggering signal for Par-1 to interact with Hpo/Sav is still unknown. It has been reported that Par-1 is activated by Tao-1 and LKB1. This study established that Par-1 antagonized Tao-1 in Hpo signaling: in Drosophila, the antagonistic relationship between Par-1 and Tao-1 in microtubule regulation has been previously reported (Liu, 2010; King, 2011; Wang, 2007). Thus, it is unlikely that Tao-1 functions as the trigger. Whether LKB1 functions as an activator of Par-1 in Hpo signaling was investigated by expressing the LKB1 transgene in different organs. Unlike Par-1, ectopic LKB1 expression limits both wing and eye growth, indicating that LKB1 is also not the trigger (Huang, 2013).

This study has shown that Par-1 and Tao-1 exhibit opposing effects on Hpo signaling. Given that Tao-1 and Par-1 are partners that regulated microtubule dynamics via the phosphorylation of Tau, Tau may have a function in Hpo signaling. To investigate this hypothesis, genetic and biochemical studies were employed, and it was found that Tau RNAi failed to suppress the expression of Hpo pathway-responsive genes. In addition, Tau did not trigger Hpo phosphorylation and Sav dissociation in vitro, indicating that Par-1 regulates Hpo signaling independent of Tau. Interestingly, it has been previously suggested that Par-1 does not regulate Tau activity in Drosophila, indicating an evolutionary difference between Par-1 and Tau-1 function (Huang, 2013).

This study has provided evidence that Par-1 regulates Hpo signaling via the phosphorylation of Hpo or the destruction of the Hpo/Sav complex. Because Par-1 is a well-known polarity regulator and polarity components, such as Crumb and Lgl, have been shown to be involved in the Hpo signaling pathway, it is possible that Par-1 may regulate Hpo signaling via a polarity complex, or its activity might be regulated via a polarity complex. Indeed, the localization of Crumb and Patj were affected by Par-1 expression. Thus, further studies on polarity complexes and Hpo signaling will help elucidate this problem (Huang, 2013).

JNK pathway activation is controlled by Tao/TAOK3 to modulate ethanol sensitivity

Neuronal signal transduction by the JNK MAP kinase pathway is altered by a broad array of stimuli including exposure to the widely abused drug ethanol, but the behavioral relevance and the regulation of JNK signaling is unclear. This study demonstrates that JNK signaling functions downstream of the Sterile20 kinase family gene tao/Taok3 to regulate the behavioral effects of acute ethanol exposure in both the fruit fly Drosophila and mice. In flies tao is required in neurons to promote sensitivity to the locomotor stimulant effects of acute ethanol exposure and to establish specific brain structures. Reduced expression of key JNK pathway genes substantially rescued the structural and behavioral phenotypes of tao mutants. Decreasing and increasing JNK pathway activity resulted in increased and decreased sensitivity to the locomotor stimulant properties of acute ethanol exposure, respectively. Further, JNK expression in a limited pattern of neurons that included brain regions implicated in ethanol responses was sufficient to restore normal behavior. Mice heterozygous for a disrupted allele of the homologous Taok3 gene (Taok3Gt) were resistant to the acute sedative effects of ethanol. JNK activity was constitutively increased in brains of Taok3Gt/+ mice, and acute induction of phospho-JNK in brain tissue by ethanol was occluded in Taok3Gt/+ mice. Finally, acute administration of a JNK inhibitor conferred resistance to the sedative effects of ethanol in wild-type but not Taok3Gt/+ mice. Taken together, these data support a role of a TAO/TAOK3-JNK neuronal signaling pathway in regulating sensitivity to acute ethanol exposure in flies and in mice (Kapfhamer, 2012).

Maternal Nanos represses hid/skl-dependent apoptosis to maintain the germ line in Drosophila embryos

Nanos (Nos) is an evolutionarily conserved protein essential for the survival of primordial germ cells. In Drosophila, maternal Nos partitions into pole cells and suppresses apoptosis to permit proper germ-line development. However, how this critical event is regulated by Nos has remained elusive. This study reports that Nos represses apoptosis of pole cells by suppressing translation of head involution defective (hid), a member of the RHG gene family that is required for Caspase activation. In addition, it is demonstrated that hid acts in concert with another RHG gene, sickle (skl), to induce apoptosis. Expression of skl is induced in pole cells by maternal tao-1, a ste20-like serine/threonine kinase. Tao-1-dependent skl expression is required to potentiate hid activity. However, skl expression is largely suppressed in normal pole cells. Once the pole cells lack maternal Nos, Tao-1-dependent skl expression is fully activated, suggesting that skl expression is also restricted by Nos. These findings provide the first evidence that the germ line is maintained through the regulated expression of RHG genes (Sato, 2007).

The connection between Nos and apoptosis of primordial germ cells (PGCs) has special significance because PGCs lacking Nos activity are eliminated by apoptosis in a variety of species, such as mouse, zebrafish, nematode, and fruit fly. In Drosophila, pole cells lacking maternal Nos enter the apoptotic pathway and are unable to migrate properly into the embryonic gonads. This migration defect is rescued by inhibiting apoptosis). Nos inhibits apoptosis of pole cells to permit their proper migration into the gonads. Thus, determining how Nos suppresses apoptosis of PGCs is critical to understanding the evolutionarily conserved mechanism of germ-line maintenance. This study presents several lines of evidence demonstrating that Nos represses apoptosis of pole cells by suppressing translation of hid RNA (Sato, 2007).

Hid is a member of the RHG gene family. These proteins share a common motif at their N terminus. This motif, referred to as the RHG motif, is essential for the ability of RHG proteins to induce apoptosis. The RHG motif interacts with the BIR (baculovirus IAP repeat) domain of Diap1 (Drosophila inhibitor of apoptosis protein 1) to oppose BIR-mediated caspase inhibition. Hid and two other RHG genes, reaper and grim, are expressed from the genomic locus H99. Deletion of this region completely inhibits apoptosis of nos pole cells. In situ hybridization analysis reveals that hid is zygotically expressed in pole cells, whereas two other RHG genes are transcribed at only trace levels, if at all. Mutations in hid rescue apoptosis of almost all of nos pole cells, consistent with this gene, among the RHG genes present at H99, playing a major role in regulating apoptosis in nos pole cells. In addition, it is demonstrated that maternal Nos represses translation of hid mRNA in pole cells. Deletion of the NRE-like sequence in hid 3' UTR abrogates Nos-dependent translational repression and effectively induces apoptosis in normal pole cells. It is concluded that Nos represses hid translation to suppress apoptosis in pole cells (Sato, 2007).

In the pole cells lacking Nos, hid acts with the fourth RHG gene, skl, to induce apoptosis. Skl expression is activated in pole cells by maternal tao-1. Overexpression of skl or tao-1 promotes apoptosis in nos pole cells. Conversely, reducing Tao-1 activity down-regulates skl expression and prevents apoptosis in nos pole cells. Additional experiments will be necessary to determine whether reducing skl expression is alone sufficient to rescue the apoptotic defect of nos pole cells as mutants for skl are not currently available. In the absence of hid activity, skl overexpression is unable to promote apoptosis in pole cells. Similar findings have been reported in embryos and the developing eye. In normal embryos, skl RNA is not expressed by all somatic cells that are destined to undergo apoptosis, and the physiological levels of skl expression are not sufficient alone to induce apoptosis in the absence of rpr, hid, and grim. Furthermore, expression of skl does not effectively induce apoptosis in the developing eye, but it enhances the effect of grim and rpr. Thus, skl potentiates the activity of the other RHG genes to produce a maximal apoptotic effect in pole cells, as well as in somatic tissues (Sato, 2007).

This study demonstrates that skl expression is induced in pole cells by maternal Tao-1, but its expression is largely suppressed in normal pole cells. Once the pole cells lack maternal Nos, skl expression is fully activated. These results suggest that Nos restricts Tao-1-dependent skl expression in pole cells. However, Nos may not suppress production of Tao-1 directly, because tao-1(D168D) and tao-1(D168A) mRNAs with intact 3' UTR were translated in pole cells even in the presence of Nos. Thus, it is speculated that Nos suppresses expression of effectors downstream of Tao-1. In mammals, Tao-1 and its related proteins signal through the p38 MAPK pathway by activating MKK3. The p38 MAPK pathway contributes to a broad variety of cellular processes, including apoptosis, by regulating gene expression. Therefore, Tao-1 may induce skl expression in pole cells via MKK3 and the p38 MAPK pathway. This model is supported by the observation that a Drosophila homolog of MKK3/6, (lic), is expressed in migrating pole cells. Alternatively, Drosophila Tao-1 may promote expression of skl through the JNK MAPK pathway, because human Tao-1 related kinase, PSK, stimulates MKK4, MKK7, and the JNK MAPK pathway (Moore, 2000). It is interesting to note that lic has been identified as a mRNA associated with Pumilio, a cofactor for Nos-dependent translational repression. Accordingly, Nos may reduce skl expression by suppressing Lic production in pole cells. Future studies will be required to test this possibility and examine the role of the MKK proteins in apoptosis downstream of Tao-1 activity in pole cells (Sato, 2007).

This study demonstrates that hid is expressed in pole cells independent of Nos activity, but its translation is repressed by Nos. Maternal tao-1 RNA is enriched in the germ plasm and inherited by pole cells. However, Tao-1-dependent skl expression is suppressed in normal pole cells. In the absence of functional Nos, Tao-1-dependent skl expression and hid translation are both derepressed, and these protein products act together to induce apoptosis. Although the mechanism by which hid transcription is activated in pole cells has remained elusive, pole cells are competent to undergo apoptosis, and reducing Nos activity effectively triggers programmed cell death. Given that maternal Nos is also involved in repressing somatic cell fate in pole cells to permit their proper germ-line development, it is proposed that apoptosis eliminates pole cells with reduced Nos activity to maintain germ-line integrity. Similarly, in mouse, apoptosis occurs in PGCs that leave the germ-line fate in response to genetic and environmental perturbations. Furthermore, Nos is involved in repressing apoptosis of PGCs in various animal species. This data provides an important first step toward understanding the evolutionarily conserved mechanisms for regulating apoptosis in the germ line (Sato, 2007).


REFERENCES

Search PubMed for articles about Drosophila Tao

Boggiano, J. C., Vanderzalm, P. J. and Fehon, R. G. (2011). Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway. Dev Cell 21: 888-895. PubMed ID: 22075147

Gomez, J. M., Wang, Y. and Riechmann, V. (2012). Tao controls epithelial morphogenesis by promoting Fasciclin 2 endocytosis. J Cell Biol 199: 1131-1143. PubMed ID: 23266957

Halder, G. and Johnson, R. L. (2011). Hippo signaling: growth control and beyond. Development 138: 9-22. PubMed ID: 21138973

Huang, H. L., Wang, S., Yin, M. X., Dong, L., Wang, C., Wu, W., Lu, Y., Feng, M., Dai, C., Guo, X., Li, L., Zhao, B., Zhou, Z., Ji, H., Jiang, J., Zhao, Y., Liu, X. Y. and Zhang, L. (2013). Par-1 regulates tissue growth by influencing hippo phosphorylation status and hippo-salvador association. PLoS Biol 11: e1001620. PubMed ID: 23940457

Huang, X., Shi, L., Cao, J., He, F., Li, R., Zhang, Y., Miao, S., Jin, L., Qu, J., Li, Z. and Lin, X. (2014). The sterile 20-like kinase tao controls tissue homeostasis by regulating the hippo pathway in Drosophila adult midgut. J Genet Genomics 41: 429-438. PubMed ID: 25160975

Johne, C., Matenia, D., Li, X. Y., Timm, T., Balusamy, K. and Mandelkow, E. M. (2008). Spred1 and TESK1--two new interaction partners of the kinase MARKK/TAO1 that link the microtubule and actin cytoskeleton. Mol Biol Cell 19: 1391-1403. PubMed ID: 18216281

Kapfhamer, D., King, I., Zou, M. E., Lim, J. P., Heberlein, U. and Wolf, F. W. (2012). JNK pathway activation is controlled by Tao/TAOK3 to modulate ethanol sensitivity. PLoS One 7: e50594. PubMed ID: 23227189

King, I., Tsai, L. T., Pflanz, R., Voigt, A., Lee, S., Jackle, H., Lu, B. and Heberlein, U. (2011). Drosophila tao controls mushroom body development and ethanol-stimulated behavior through par-1. J Neurosci 31: 1139-1148. PubMed ID: 21248138

Liu, T., Rohn, J. L., Picone, R., Kunda, P. and Baum, B. (2010). Tao-1 is a negative regulator of microtubule plus-end growth. J Cell Sci 123: 2708-2716. PubMed ID: 20647372

Mitsopoulos, C., Zihni, C., Garg, R., Ridley, A. J. and Morris, J. D. (2003). The prostate-derived sterile 20-like kinase (PSK) regulates microtubule organization and stability. J Biol Chem 278: 18085-18091. PubMed ID: 12639963

Moore, T. M., Garg, R., Johnson, C., Coptcoat, M. J., Ridley, A. J. and Morris, J. D. (2000). PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization. J Biol Chem 275: 4311-4322. PubMed ID: 10660600

Poon, C. L., Lin, J. I., Zhang, X. and Harvey, K. F. (2011). The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway. Dev Cell 21: 896-906. PubMed ID: 22075148

Sato, K., Hayashi, Y., Ninomiya, Y., Shigenobu, S., Arita, K., Mukai, M. and Kobayashi, S. (2007). Maternal Nanos represses hid/skl-dependent apoptosis to maintain the germ line in Drosophila embryos. Proc Natl Acad Sci U S A 104: 7455-7460. PubMed ID: 17449640

Timm, T., Li, X. Y., Biernat, J., Jiao, J., Mandelkow, E., Vandekerckhove, J. and Mandelkow, E. M. (2003). MARKK, a Ste20-like kinase, activates the polarity-inducing kinase MARK/PAR-1. EMBO J 22: 5090-5101. PubMed ID: 14517247

Wang, J. W., Imai, Y. and Lu, B. (2007). Activation of PAR-1 kinase and stimulation of tau phosphorylation by diverse signals require the tumor suppressor protein LKB1. J Neurosci 27: 574-581. PubMed ID: 17234589

Yasuda, S., Tanaka, H., Sugiura, H., Okamura, K., Sakaguchi, T., Tran, U., Takemiya, T., Mizoguchi, A., Yagita, Y., Sakurai, T., De Robertis, E. M. and Yamagata, K. (2007). Activity-induced protocadherin arcadlin regulates dendritic spine number by triggering N-cadherin endocytosis via TAO2beta and p38 MAP kinases. Neuron 56: 456-471. PubMed ID: 17988630

Yu, J., Zheng, Y., Dong, J., Klusza, S., Deng, W. M. and Pan, D. (2010). Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell 18: 288-299. PubMed ID: 20159598

Zihni, C., Mitsopoulos, C., Tavares, I. A., Baum, B., Ridley, A. J. and Morris, J. D. (2007). Prostate-derived sterile 20-like kinase 1-alpha induces apoptosis. JNK- and caspase-dependent nuclear localization is a requirement for membrane blebbing. J Biol Chem 282: 6484-6493. PubMed ID: 17158878


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date revised: 3 December 2014

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