InteractiveFly: GeneBrief

Ankyrin-repeat, SH3-domain, and Proline-rich-region containing Protein: Biological Overview | References

BIOLOGICAL OVERVIEW

Adherens junctions (AJs) provide structure to epithelial tissues by connecting adjacent cells through homophilic E-cadherin interactions and are linked to the actin cytoskeleton via the intermediate binding proteins beta-catenin and alpha-catenin. Rather than being static structures, AJs are extensively remodeled during development, allowing the cell rearrangements required for morphogenesis. Several 'noncore' AJ components have been identified that modulate AJs to promote this plasticity but are not absolutely required for cell-cell adhesion. dASPP has been identified as a positive regulator of dCsk (Drosophila C-terminal Src kinase) (Langton, 2007). This study shows that dRASSF8, the Drosophila RASSF8 homolog, binds to dASPP and that this interaction is required for normal dASPP levels. genetic and biochemical data suggest that dRASSF8 acts in concert with dASPP to promote dCsk activity. Both proteins specifically localize to AJs and are mutually required for each other's localization. Furthermore, abnormal E-cadherin localization is observed in mutant pupal retinas, correlating with aberrant cellular arrangements. Loss of dCsk or overexpression of Src elicited similar AJ defects. Because Src is known to regulate AJs in both Drosophila and mammals, it is proposed that dASPP and dRASSF8 fine tune cell-cell adhesion during development by directing dCsk and Src activity. The dASPP-dRASSF8 interaction is conserved in humans, suggesting that mammalian ASPP1/2 and RASSF8, which are candidate tumor-suppressor genes, restrict the activity of the Src proto-oncogene (Langton, 2009).

Cell-cell contacts are essential for development and adult life of multicellular organisms. The best-characterized form of cell-cell contact is the adherens junction (AJ), which links neighboring cells via homotypic E-cadherin (E-Cad) interactions. The highly conserved intracellular domain of E-Cad binds to β-catenin, which itself binds to α-catenin. Transient interactions between α-catenin and actin filaments link AJs to the cytoskeleton, though the exact nature of this connection remains controversial. AJs are particularly important for the integrity of epithelial tissues. In addition to establishing and maintaining cell-cell adhesion, AJs regulate several aspects of cellular behavior, including cytoskeletal rearrangement and transcription. Inappropriate disruption of cell-cell contacts can lead to excess proliferation and is a hallmark of the metastatic process (Langton, 2009).

Dynamic remodeling of AJs occurs during all major morphogenetic events involving movement and rearrangement of epithelial cells, including convergent extension and gastrulation. AJ remodeling is necessary for the generation of epithelial structures with extremely precise patterns, such as the hexagonal array of ommatidia in the Drosophila compound eye (Langton, 2009).

SRC signaling is a major cellular pathway known to promote AJ remodeling in development and metastasis. Cellular SRC (c-SRC) is a member of the SRC family kinases (SFKs), which include c-SRC, FYN, and YES. Activated c-SRC is known to regulate AJs by several mechanisms. For example, c-SRC can induce the ubiquitylation of E-Cad by an E3 ubiquitin ligase called Hakai, promoting E-Cad internalization or degradation. In Drosophila, Src42A (one of two c-Src homologs) genetically interacts with E-Cad (encoded by shotgun [shg] in Drosophila), localizes to AJs, and forms a ternary complex with E-Cad and Armadillo (Drosophila β-catenin). Furthermore, Src42A activation leads to decreased E-Cad protein levels and concurrent stimulation of E-Cad transcription by Armadillo and TCF, which is thought to be important for AJ turnover during morphogenesis (Langton, 2009).

The C-terminal region of c-SRC and other SFKs is targeted by C-terminal SRC kinase (CSK), which negatively regulates c-SRC by phosphorylating a conserved tyrosine residue (Tyr527 in avian c-SRC). Drosophila CSK (dCsk) appears to function analogously to mammalian CSK as a negative regulator of SFKs. dCsk is a negative regulator of tissue growth; mutants die as giant pupae and imaginal discs are enlarged as a result of increased proliferation. These observations are seemingly at odds with studies showing that Src activation in Drosophila tissues stimulates proliferation but also leads to considerable apoptosis. A recent report attempted to reconcile this discrepancy, suggesting that lower levels of Src activation induce proliferation and protection from apoptosis, whereas high levels lead to apoptosis and invasive migration (Vidal, 2007; Langton, 2009 and references therein).

It has been shown that dCsk activity is modulated by dASPP, the Drosophila homolog of mammalian ASPP1 and ASPP2, which physically interacts with dCsk and enhances its capacity to phosphorylate Src42A (Langton, 2007). Accordingly, dASPP phenotypes are enhanced by reducing dCsk gene dosage and are rescued by complete removal of Src64B, which functions redundantly with Src42A. This study identifies dRASSF8 as a new dASPP regulator. dRASSF8 is the homolog of mammalian RASSF7/8 (Ras association domain family 7/8). Ras association (RA) domain-containing proteins are putative Ras effectors; they specifically bind the activated (GTP-bound) form of Ras family GTPases, which function in numerous signal transduction pathways regulating proliferation, apoptosis, and differentiation. Mammalian RASSF family members 1–6 are characterized by their domain structure, with a C-terminal RA domain, a C1-like zinc finger, and a SARAH (Salvador-RASSF-Hippo) domain (van der Weyden, 2007). Mammalian RASSF7–10 are atypical RASSF proteins because they contain an N-terminal RA domain and lack a C1-like or SARAH domain. Recently, Xenopus RASSF7 was shown to be required for completing mitosis (Sherwood, 2008). Human RASSF8 is a putative tumor-suppressor gene; when expressed in lung cancer cells, RASSF8 inhibits anchorage-independent growth (Falvella, 2006). Importantly, the molecular function of RASSF8 has not been elucidated (Langton, 2009).

Two RASSF family proteins are encoded by the Drosophila genome. dRASSF is similar to human RASSF1–6 and has been linked to the Hippo pathway (Polesello, 2006). dRASSF8 is similar to human RASSF7 and RASSF8, having an N-terminal RA domain. Published genome-wide yeast two-hybrid data suggested that dRASSF8 interacts with dASPP, prompting an investigation of the relationship between these proteins. Based on genetic and biochemical data, it is suggested that the dASPP-dRASSF8 complex regulates AJs by directing the activity of dCsk and Src (Langton, 2009).

dRASSF8 is the sole Drosophila homolog of mammalian RASSF7 and RASSF8, which are so-called N-terminal RASSF proteins and the least-studied members of the RASSF family. This study demonstrates that dRASSF8 binds to dASPP in Drosophila cells and that RASSF8 binds to ASPP1 and ASPP2 in human cells, indicating that an evolutionarily conserved relationship between these proteins has been uncovered. The function of RASSF8 is currently unknown, and this study thus provides new insights into the function of N-terminal RASSF proteins (Langton, 2009).

Future experiments will determine whether RASSF7 also binds ASPP family proteins or whether this function is specific to RASSF8. RASSF7 has been studied in Xenopus and was found to associate with centrosomes and to be required for completing mitosis. In contrast, the current data suggest that dRASSF8 is not required for cell-cycle progression because null mutants for dRASSF8 are viable. These findings are suggestive of divergent functions for RASSF7 and RASSF8 in vertebrates, with dRASSF8 being functionally analogous to RASSF8 rather than RASSF7. Indeed, GFP-tagged RASSF7 localizes to the nucleus and centrosomes in Xenopus embryos, whereas this study never observed nuclear localization of dRASSF8. Further studies of N-terminal RASSF proteins in vertebrates should clarify whether RASSF7 and RASSF8 have overlapping or independent functions (Langton, 2009).

In vivo data point at a close relationship between dRASSF8 and dASPP, which colocalize and are required for each other's presence at AJs in epithelial cells. dRASSF8 posttranscriptionally regulates the levels of dASPP protein in epithelia. Thus, it seems likely that binding to dRASSF8 stabilizes dASPP and prevents its degradation, which can be observed for many protein complexes. Overall, these data provide compelling evidence for a functional link between dRASSF8 and dASPP, which is likely to be conserved through to their closest mammalian counterparts, RASSF8 and ASPP1/2 (Langton, 2009).

The data suggest that dRASSF8 has some dASPP-independent roles. For example, dRASSF8 mutant wings are large and broadened, whereas dASPP mutant wings are large but of normal shape. In addition, the dRASSF8 adult eye phenotype is more marked than that of dASPP mutants. Accordingly, it was found that dRASSF8, but not dASPP, is required for apoptosis of excess IOCs in the developing pupal retina. It therefore appears that the dRASSF8 eye phenotype results from both reduced apoptosis of IOCs and cell-cell adhesion defects. The subtle differences between the dASPP and dRASSF8 phenotypes indicate unknown functions for dRASSF8, which are not due to its effects on dASPP. Future efforts will be aimed at elucidating these functions (Langton, 2009).

These data are consistent with a model in which dRASSF8 binds to and positively regulates dASPP and, in this way, promotes dCsk activity indirectly. Coimmunoprecipitation experiments support this idea, showing that dRASSF8 and dASPP associate and that dASPP and dCsk associate. However, no detect interaction was detected between dRASSF8 and dCsk, indicating that dRASSF8 does not directly associate with dCsk. The proposed model is also supported by genetic data; the dRASSF8-dCsk genetic interaction is weaker than the dASPP-dCsk interaction, suggesting that dASPP is the primary regulator of dCsk. The weaker genetic relationship between dRASSF8 and dCsk can be explained by the observation that some dASPP protein persists in dRASSF8 mutant tissue. These observations suggest that dRASSF8 regulates dCsk via dASPP (Langton, 2009).

Retinal morphogenesis involves dynamic changes in cell-cell contacts to create the final ordered array of photoreceptors and accessory cells. dASPP and dRASSF8 are required for normal E-Cad localization in 26-27 hr APF retinas, providing an explanation for the patterning defects in mutant eyes. It is proposed that the abnormal E-Cad localization in dASPP mutant eyes results from increased Src activity based on several lines of evidence. dASPP binds to and positively regulates dCsk, leading to Src inhibition; therefore, loss of dASPP increases Src activity, which is known to reduce cell-cell adhesion by promoting the internalization and degradation of E-Cad. In agreement with this, it was shown that loss of dCsk or overexpression of either Drosophila Src leads to loss of AJ material in 26-27 hr APF retinas. This claim is further supported by the fact that the dASPP eye phenotype is suppressed by loss of Src64B. Thus, the presence of the dASPP-dRASSF8 complex at AJs may be required to locally prevent inappropriate Src activation and dissolution of AJs (Langton, 2009).

The fact that dASPP and dRASSF8 mutants are homozygous viable implies that these genes are dispensable for the majority of morphogenetic processes occurring during development. Therefore, the regulation of AJs by dASPP and dRASSF8 may be restricted to the eye. However, as they are expressed in other epithelial tissues, a closer examination of dASPP and dRASSF8 mutants may reveal subtle defects in other morphogenetic processes (Langton, 2009).

It is suggested that dASPP and dRASSF8 are new noncore AJ components and part of the machinery that ensures the fine regulation of AJs by Src during development. This regulation is crucial to provide precisely the right amount of junctional plasticity to allow cell-cell rearrangements and patterning to take place while limiting this plasticity to maintain epithelial coherence and prevent cell delamination. Because the interaction between these proteins is conserved in mammals, this finding is likely to be relevant to mammalian development and to the metastatic process, which is associated with downregulation of E-Cad and loss of cell-cell adhesions. Indeed, ASPP1 knockout mice present defects in the assembly of lymphatic vessels consistent with a potential adhesion defect (Hirashima, 2008). This suggests that regulation of cell-cell adhesion may underlie the function of ASPP1/2 and RASSF8 as mammalian tumor suppressors (Langton, 2009).

Drosophila ASPP regulates C-terminal Src kinase activity

Src-family kinases (SFKs) control a variety of biological processes, from cell proliferation and differentiation to cytoskeletal rearrangements. Abnormal activation of SFKs has been implicated in a wide variety of cancers and is associated with metastatic behavior (Yeatman, 2004). SFKs are maintained in an inactive state by inhibitory phosphorylation of their C-terminal region by C-terminal Src kinase (Csk). Drosophila Ankyrin-repeat, SH3-domain, and Proline-rich-region containing Protein (dASPP) has been identified as a regulator of Drosophila Csk (dCsk) activity. dASPP is the homolog of the mammalian ASPP proteins, which are known to bind to and stimulate the proapoptotic function of p53. dASPP is shown to be a positive regulator of dCsk. First, dASPP loss-of-function strongly enhances the specific phenotypes of dCsk mutants in wing epithelial cells. Second, dASPP interacts physically with dCsk to potentiate the inhibitory phosphorylation of Drosophila Src (dSrc). These results suggest a role for dASPP in maintaining epithelial integrity through dCsk regulation (Langton, 2007).

The Src protein tyrosine kinase was first identified as the viral oncogene of the Rous-Sarcoma virus, v-src. Src-family kinases (SFKs), which include c-Src, Fyn, and Lck, are implicated in different cellular processes, and abnormal activation of SFKs has been associated with tumor development and with metastatic behavior (Yeatman, 2004). C-terminal Src kinase (Csk) maintains SFKs in an inactive state by an inhibitory phosphorylation (Tyr527 in avian c-Src) (Cole, 2003). This phosphorylation event triggers autoinhibition of the Src kinase domain through binding of Src's SH2 domain to the phospho-Tyrosine. Tyr527 is deleted in the v-src oncogene, underlining the biological significance of Src regulation by Csk. The csk mutant mouse phenotype is partially suppressed by loss of src, suggesting that these proteins do indeed act in concert in vivo (Thomas, 1995). Importantly, the regulation of Csk is not well understood at present (Langton, 2007).

Drosophila has emerged as a useful genetic model system in which many aspects of tumor formation can be studied, including excess proliferation, evasion of apoptosis, and tumor cell invasion and metastasis. Drosophila Csk (dCsk) has been reported to function as a tumor-suppressor gene. dCsk mutants display excess cell proliferation and overgrowth defects primarily due to activation of targets of Drosophila Src kinases (Src64B and Src42A), including c-Jun N-terminal kinase (JNK), Stat, and Btk29A (Bruton's Tyrosine Kinase29A/Tec29A) (Pedraza, 2004, Read, 2004). More recently, it has been shown that local inactivation of dCsk in small patches surrounded by normal cells surprisingly does not cause overgrowth (Vidal, 2006). Instead, these cells move to a basal position in the epithelium and spread among the wild-type cells while simultaneously undergoing apoptosis, which may reflect the function of dSrc in promoting motility and invasion (Langton, 2007).

dASPP as a regulator of dCsk activity. dASPP is the homolog of mammalian ASPP1 and -2 (Ankyrin-repeat, SH3-domain and Proline-rich-region containing Protein). ASPP1 and -2 have been reported to bind to p53 via their ankyrin and SH3 motifs (Iwabuchi, 1994, Samuels-Lev, 2001). Binding of ASPP1 or -2 to p53 is thought to specifically potentiate its transcriptional activity on proapoptotic targets such as the Bcl-family gene Bax, but not on cell cycle targets like p21 (Samuels-Lev, 2001). Both the postnatal lethality of ASPP2^-/- mice and the tumor-prone phenotype of ASPP2 heterozygotes are enhanced by loss of p53, suggesting that the p53-ASPP interaction is biologically significant (Vives, 2006). Deregulation of ASPP gene expression has been reported in several different cancers (Trigiante, 2006), underlining the importance of these as tumor suppressor loci (Langton, 2007).

This study generated and characterized dASPP mutants, which are homozygous viable and exhibit an overgrowth phenotype due to an increased number of cells of normal size. Several lines of evidence are presented suggesting that dASPP positively regulates dCsk activity. First, dCsk mutant phenotypes are strongly enhanced by dASPP loss of function. Second, dASPP physically interacts with dCsk. Third, dCsk kinase activity on dSrc is potentiated in the presence of dASPP (Langton, 2007).

In Drosophila dASPP funcions as an important regulator of dSrc by binding to and potentiating the kinase activity of dCsk. dASPP and dCsk mutants show similar phenotypes, namely excess proliferation, increased mass, developmental delay, and an alteration in cell-cell adhesion properties that results in mispatterning of the retina. dCsk has a stronger phenotype than dASPP. For example, dCsk mutants die as enlarged pupae, whereas dASPP mutant flies are viable with a more modest increase in size. This suggests that dASPP is not absolutely required for dCsk function but is necessary for maximal signaling (Langton, 2007).

How does dASPP promote dCsk activity? Mammalian Csk's ability to phosphorylate Src is believed to be primarily determined by its translocation to lipid rafts, where Src is tethered by virtue of its myristylated N terminus (Cole, 2003). The transmembrane protein Cbp (Csk-binding protein or PAG) has been reported to recruit Csk to lipid rafts (Kawabuchi, 2000). It will be interesting to determine whether dASPP can regulate dCsk localization. Alternatively, dASPP could control dCsk activity through a conformational change or by recruiting other proteins to dCsk (Langton, 2007).

Human ASPP proteins have been shown to directly bind to and regulate the apoptotic function of p53 (Samuels-Lev, 2001). Therefore whether dASPP is capable of binding to Drosophila p53 (Dmp53) was examined. No interaction was shown between dASPP and Dmp53 in coimmunoprecipitation experiments. Additionally, it was found that dASPP is not required for radiation-induced cell death, which is mediated via Dmp53 activation. These results suggest that the human p53-activating function of ASPP is not conserved in Drosophila and may have evolved later. Indeed, neither the four human p53 residues shown in crystallography studies to contact ASPP2 (His¹⁷⁸, Arg¹⁸¹, Met²⁴³ and Asn²⁴⁷) (Gorina, 1996) nor the proline-rich region shown to be a second site for binding between the two proteins (Bergamaschi, 2003) are conserved in Dmp53 (Langton, 2007).

Vidal (2006) has shown that dCsk mutant cells are susceptible to apoptosis only when in contact with wild-type tissue. Perturbation of dASPP/dCsk signaling in discrete areas of the wing disc induces apoptosis of mutant cells. However, the data shows that broad loss of dCsk in wing discs also results in considerable apoptosis. This suggests that epithelial extrusion and cell death may not only occur at mutant/wild-type clone boundaries but is more a general phenotype of dCsk mutant cells. Accordingly, it was found that dCsk^1jd8 mutant eyes are often overgrown but occasionally present a small eye phenotype, presumably as a result of massive apoptosis. Since this phenotype is sensitive to the dosage of btk and levels of JNK signaling, it is likely to be a consequence of ectopic activation of dSrc in dCsk mutant discs. Indeed, dSrc overexpression leads to JNK activation and apoptosis (Langton, 2007).

JNK activation in response to loss of apico-basal polarity has been reported to promote invasion and growth in cells expressing oncogenic Ras (Igaki, 2006). Protection of dCsk mutant cells from apoptosis (for example, by oncogenic Ras) might promote their metastatic potential. Such collaboration between multiple oncogenes/tumor suppressors is a necessary step in tumor progression in humans (Langton, 2007).

dCsk likely functions to maintain epithelial polarity by preventing dSrc from dissolving adherens junctions and inducing JNK activation, as suggested by mammalian and Drosophila studies (Vidal, 2006, Yeatman, 2004). Src activation has been reported to promote epithelial-mesenchymal transition, a process whereby epithelial cells lose polarity and become invasive (Avizienyte, 2005). This process is similar to the loss of polarity and cell spreading observed in Drosophila epithelial cells where dASPP/dCsk signaling is disrupted (Vidal, 2006). Interestingly, ASPP2 has been reported to be downregulated in invasive and metastatic breast carcinoma cells (Sgroi, 1999). The current results provide a potential mechanism for ASSP's role in tumor cell invasion (Langton, 2007).

In summary, this study has shown that dASPP and dCsk interact physically and genetically and that this interaction is important for maintenance of cells within the developing wing epithelium. These results provide a link between two previously unrelated tumor suppressors (Langton, 2007).

The Lats2 tumor suppressor augments p53-mediated apoptosis by promoting the nuclear proapoptotic function of ASPP1

Apoptosis is an important mechanism to eliminate potentially tumorigenic cells. The tumor suppressor p53 plays a pivotal role in this process. Many tumors harbor mutant p53, but others evade its tumor-suppressive effects by altering the expression of proteins that regulate the p53 pathway. ASPP1 (apoptosis-stimulating protein of p53-1) is a key mediator of the nuclear p53 apoptotic response. Under basal conditions, ASPP1 is cytoplasmic. In response to oncogenic stress, the tumor suppressor Lats2 (large tumor suppressor 2) phosphorylates ASPP1 and drives its translocation into the nucleus. Together, Lats2 and ASPP1 shunt p53 to proapoptotic promoters and promote the death of polyploid cells. These effects are overridden by the Yap1 (Yes-associated protein 1) oncoprotein, which disrupts Lats2-ASPP1 binding and antagonizes the tumor-suppressing function of the Lats2/ASPP1/p53 axis (Aylon, 2010).

Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP

The ASPP (apoptosis-stimulating protein of p53) family of proteins can function in the nucleus to modulate the transcriptional activity of p53, with ASPP1 and ASPP2 contributing to the expression of apoptotic target genes. This study describes a new function for cytoplasmic ASPP1 in controlling YAP (Yes-associated protein)/TAZ. ASPP1 can inhibit the interaction of YAP with LATS1 (large tumor suppressor 1), a kinase that phosphorylates YAP/TAZ and promotes cytoplasmic sequestration and protein degradation. This function of ASPP1 therefore enhances nuclear accumulation of YAP/TAZ and YAP/TAZ-dependent transcriptional regulation. The consequence of YAP/TAZ activation by ASPP1 is to inhibit apoptosis, in part through the down-regulation of Bim expression, leading to resistance to anoikis and enhanced cell migration. These results reveal a potential oncogenic role for cytoplasmic ASPP1, in contrast to the tumor-suppressive activity described previously for nuclear ASPP1 (Vigneron, 2010).

Search PubMed for articles about Drosophila ASPP

Avizienyte, E. and Frame, M. C. (2005). Src and FAK signalling controls adhesion fate and the epithelial-to-mesenchymal transition. Curr. Opin. Cell Biol. 17(5): 542-7. PubMed ID: 16099634

Aylon, Y., et al. (2010). The Lats2 tumor suppressor augments p53-mediated apoptosis by promoting the nuclear proapoptotic function of ASPP1. Genes Dev. 24(21):2420-9. PubMed ID: 21041410

Bergamaschi, D., Samuels, Y., O'Neil, N.J., Trigiante, G., Crook, T., Hsieh, J.-K., O'Connor, D.J., Zhong, S., Campargue, I. and Tomlinson, M.L. (2003). iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat. Genet. 33: 162-167. PubMed citation: 12524540

Cole, P. A., Shen, K., Qiao, Y. and Wang, D. (2003). Protein tyrosine kinases Src and Csk: a tail's tale. Curr. Opin. Chem. Biol. 7: 580-585. PubMed citation: 14580561

Falvella, F. S., et al. (2006). Identification of RASSF8 as a candidate lung tumor suppressor gene. Oncogene 25: 3934-3938. PubMed ID: 16462760

Gorina, S., and Pavletich, N. P. (1996). Structure of the p53 tumor suppressor bound to the ankyrin and SH3 domains of 53BP2. Science 274: 1001-1005. PubMed citation: 8875926

Hirashima, M., et al. (2008). Lymphatic vessel assembly is impaired in Aspp1-deficient mouse embryos. Dev. Biol. 316: 149-159. PubMed ID: 18304521

Igaki, T., Pagliarini, R.A. and Xu, T. (2006). Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr. Biol. 16: 1139-1146. PubMed citation: 16753569

Iwabuchi, K., Bartel, P.L., Li, B., Marraccino, R. and Fields, S. (1994). Two cellular proteins that bind to wild-type but not mutant p53. Proc. Natl. Acad. Sci. 91: 6098-6102. PubMed citation: 8016121

Kawabuchi, M., Satomi, Y., Takao, T., Shimonishi, Y., Nada, S., Nagai, K., Tarakhovsky, A. and Okada, M. (2000). Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature 404: 999-1003. PubMed citation: 10801129

Langton, P. F., Colombani, J., Aerne, B. L. and Tapon, N. (2007). Drosophila ASPP regulates C-terminal Src kinase activity. Dev. Cell 13: 773-782. PubMed citation: 18061561

Langton, P. F., et al. (2009). The dASPP-dRASSF8 complex regulates cell-cell adhesion during Drosophila retinal morphogenesis. Curr. Biol. 19(23): 1969-78. PubMed ID: 19931458

Pedraza, L. G., Stewart, R. A., Li, D. M. and Xu, T. (2004). Drosophila Src-family kinases function with Csk to regulate cell proliferation and apoptosis. Oncogene 23(27): 4754-62. 15107833

Polesello, C., et al. (2006). The Drosophila RASSF homolog antagonizes the Hippo pathway. Curr. Biol. 16: 2459-2465. PubMed ID: 17174922

Read, R. D., Bach, E. A. and Cagan, R. L. (2004). Drosophila C-terminal Src kinase negatively regulates organ growth and cell proliferation through inhibition of the Src, Jun N-terminal kinase, and STAT pathways. Mol. Cell. Biol. 24: 6676-6689. 15254235

Samuels-Lev, Y., O'Connor, D. J., Bergamaschi, D., Trigiante, G., Hsieh, J.-K., Zhong, S., Campargue, I., Naumovski, L., Crook, T. and Lu, X. (2001). ASPP proteins specifically stimulate the apoptotic function of p53. Mol. Cell 8: 781-794. PubMed citation: 11684014

Sgroi, D.C., Teng, S., Robinson, G., LeVangie, R., Hudson, J.R. and Elkahloun, A.G. (1999). In vivo gene expression profile analysis of human breast cancer progression. Cancer Res. 59: 5656-5661. PubMed ID: 10582678

Sherwood, V., Manbodh, R., Sheppard, C. and Chalmers, A. D. (2008). RASSF7 is a member of a new family of RAS association domain-containing proteins and is required for completing mitosis. Mol. Biol. Cell 19: 1772-1782. PubMed ID: 18272789

Thomas, S. M., Soriano, P. and Imamoto, A. (1995). Specific and redundant roles of Src and Fyn in organizing the cytoskeleton. Nature 376: 267-271. PubMed citation: 7617039

Trigiante, G. and Lu, X. (2006). ASPPs and cancer. Nat. Rev. Cancer 6: 217-226. PubMed citation: 16498444

van der Weyden, L. and Adams, D. J. (2007). The Ras-association domain family (RASSF) members and their role in human tumourigenesis. Biochimica et Biophysica Acta 1776: 58-85. PubMed ID: 17692468

Vidal, M., Larson, D. E. and Cagan, R. L. (2006). Csk-deficient boundary cells are eliminated from normal Drosophila epithelia by exclusion, migration, and apoptosis. Dev. Cell 10: 33-44. PubMed citation: 16399076

Vidal, M., Warner, S., Read, R. and Cagan, R. L. (2007). Differing Src signaling levels have distinct outcomes in Drosophila. Cancer Res. 67: 10278-10285. PubMed ID: 17974969

Vigneron, A. M., Ludwig, R. L. and Vousden, K. H. (2010). Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP. Genes Dev. 24(21): 2430-9. PubMed ID: 21041411

Vives, V., Su, J., Zhong, S., Ratnayaka, I., Slee, E., Goldin, R. and Lu, X. (2006). ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growth. Genes Dev. 20: 1262-1267. PubMed citation: 16702401

Yeatman, T. J. (2004). A renaissance for SRC. Nat. Rev. Cancer 4: 470-480. PubMed citation: 15170449

date revised: 20 March 2011

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