InteractiveFly: GeneBrief

Numb-associated kinase: Biological Overview | References

Gene name - Numb-associated kinase

Synonyms -

Cytological map position - 37B7-37B7

Function - kinase

Keywords - endocytosis, vesicular transport, clathrin adaptor-associated kinase, promotes higher-order dendrite growth, regulates protein localization in salivary gland cells, asymmetric cell division

Symbol - Nak

FlyBase ID: FBgn0015772

Genetic map position - chr2L:18957900-18963850

Classification - PKc_like: Protein Kinases, catalytic domain

Cellular location - cytoplasmic

NCBI links: Precomputed BLAST | EntrezGene

During development, dendrites arborize in a field several hundred folds of their soma size, a process regulated by intrinsic transcription program and cell adhesion molecule (CAM)-mediated interaction. However, underlying cellular machineries that govern distal higher-order dendrite extension remain largely unknown. This study shows that Numb-associated kinase (Nak), a clathrin adaptor-associated kinase, promotes higher-order dendrite growth through endocytosis. In nak mutants, both the number and length of higher-order dendrites are reduced; these characters phenocopied by disruptions of clathrin-mediated endocytosis. Nak interacts genetically with components of the endocytic pathway, colocalizes with clathrin puncta and is required for dendritic localization of clathrin puncta. More importantly, these Nak-containing clathrin structures preferentially localize to branching points and dendritic tips that are undergoing active growth. Evidence is presented that the Drosophila L1-CAM homolog Neuroglian is a relevant cargo of Nak-dependent internalization, suggesting that localized clathrin-mediated endocytosis of CAMs facilitates the extension of nearby higher-order dendrites (Yang, 2011; see video abstract).

Postmitotic neurons elaborate highly branched, tree-like dendrites that display distinct patterns in accordance with their input reception and integration. Therefore, regulation of dendrite arborization during development is crucial for neuronal function and physiology. Dendrite morphogenesis proceeds in two main phases: lower-order dendrites first pioneer and delineate the receptive field and then higher-order dendrites branch out to fill in gaps between existing ones (Jan, 2010). This process is exemplified by the morphogenesis of Drosophila dendritic arborization (da) neurons, which have a roughly fixed pattern of lower-order dendrites in early larval stages. Higher-order dendrites then branch out to reach the order of more than six, covering the entire epidermal area. These distinct phases of dendrite arborization are manifested by the difference in underlying cytoskeletal composition. While lower-order dendrites are structurally supported by rigid microtubules, higher-order dendrites contain actin and loosely packed microtubules (Jinushi-Nakao, 2007). It is thought that the structural flexibility of higher-order dendrites allows dynamic behaviors like extension, retraction, turning and stalling to explore unfilled areas (Yang, 2011).

The da neurons are classified into four types (I-IV) according to branching pattern and complexity of dendrites. The most complex class IV da neurons have a unique pattern, in which few branches are sent out from proximal dendrites, while dendrites grow extensively in distal regions. Polarized growth of higher-order dendrites requires specialized cellular machineries. For instance, disruption of the ER-to-Golgi transport in class IV ddaC neurons preferentially shreds higher-order dendrites, suggesting that the secretory pathway is needed to sustain membrane addition during dendrite formation (Ye, 2007). Golgi outposts, hallmark of the satellite secretory pathway in dendrites, move anterogradely and retrogradely during extension and retraction of terminal dendrites, respectively. Arborization in the distal field demands active transport systems mediated by microtubule-based motors, as mutations in dynein light intermediate chain (dlic) or kinesin heavy chain (khc) fail to elaborate branches in the distal region of class IV ddaC neurons (Satoh, 2008; Zheng, 2008b). The transport of Rab5-positive endosomes allows branching of distal dendrites, suggesting that the endocytic pathway also has a role in dendrite morphogenesis (Yang, 2011).

The growth of higher-order dendrites seems to require elevated level of endocytosis. Endocytosis is more active in dendrites than in axons in cultured hippocampal neurons. Dynamic assembly and disassembly of clathrin-positive structures, indicative of active endocytosis, are seen at dendritic shafts and tips of young hippocampal neurons. These clathrin-positive structures become stabilized in mature neurons (Blanpied, 2002). Endocytosis is known to regulate the polarized distribution of the cell adhesion molecule NgCAM in hippocampal neurons, which is first transported to the somatodendritic membrane and then transcytosed to the axonal surface (Yap, 2008). Endocytosis is also important for transporting NMDAR to synaptic sites during their formation in dendrites of young cortical neurons. The NMDAR packets transported along microtubules are intermittently exposed to the membrane surface by cycles of exocytosis and endocytosis, at sites coinciding with the clathrin 'hotspots'. Endocytosis can regulate the activities of transmembrane receptors whose signaling activity is important to dendrite growth and maintenance. For instance, the neurotrophin-Trk receptor-mediated signaling that depends on endocytosis could be important for dendrite morphogenesis (Zheng, 2008a). However, how endocytosis regulates dendrite morphogenesis is not yet clear (Yang, 2011).

Clathrin-mediated endocytosis (CME) is the major route for selectively internalizing extracellular molecules and transmembrane proteins from the plasma membrane. Transmembrane cargos destined for internalization are recruited into clathrin-coated pits through interaction with appropriate clathrin adaptors. One such accessory factor is adaptor protein 2 (AP2), a heterotetrameric complex consisting of a, b, m and s subunits. AP2-dependent cargo recruitment can be regulated by reversible protein phosphorylation by actin-related kinase (Ark) family serine/threonine kinases (Smythe, 2003). In yeast, Ark family genes are known to influence endocytosis by phosphorylating Pan1, an Eps15 homolog, to regulate actin dynamics (Toshima, 2005). Mammals contain two Ark family genes, cyclin G-associated kinase (GAK) and adaptor-associated kinase 1 (AAK1) and both have been implicated in vesicular transport (Conner, 2002; Lee, 2005). GAK, best known for its role in the disassembly of clathrin coats from clathrin-coated vesicles, has multiple functions during clathrin cycle (Eisenberg, 2007). AAK1 has been shown to bind the a subunit of AP2, phosphorylate the cargo-binding m2 subunit and promote receptor-mediated transferrin uptake (Conner, 2002; Conner, 2003; Ricotta, 2002). AAK1 also participates in transferrin receptor recycling from the early/sorting endosome in a kinase activity-dependent manner (Yang, 2011).

Numb-associated kinase (Nak), the Drosophila Ark family member, contains the conserved Ark kinase domain and several motifs (DPF, DLL and NPF) mediating interactions with endocytic proteins (Conner, 2002; Peng, 2009). To study the function of Nak in development, nak deletion mutants and RNAi lines were generated and it was shown that depletion of nak activity in da neurons disrupts higher-order dendrite development. This function of Nak in dendritic morphogenesis is likely mediated through CME, as Nak exhibits specific genetic interactions with components of CME, colocalizes with clathrin in dendritic puncta and is required for the presence of clathrin puncta in distal higher-order dendrites. More importantly, live-imaging analysis shows that the presence of these clathrin/Nak puncta at basal branching sites correlates with extension of terminal branches. In addition, evidence is presented that the localization of Neuroglian (Nrg) in higher-order dendrites requires Nak, implying that regional internalization of a cell adhesion molecule is crucial for dendrite morphogenesis (Yang, 2011).

This study has shown that disruption of nak during dendrite arborization of da neurons significantly reduces both number and length of dendritic branches. Multiple classes of da neurons were analyzed for the lack of Nak activity, which suggests that its general role in higher-order dendrite morphogenesis. The function of Nak in dendrite arborization is required cell autonomously, as dendritic defects in nak mutants could be rescued by neuron-specific expression of wild-type Nak (Yang, 2011).

Several lines of evidence suggest a functional link between Nak and AP2, the endocytosis-specific clathrin adaptor, in dendrite morphogenesis. First, coimmunoprecipitation results show that Nak predominantly associates with AP2. Second, Nak colocalizea well with GFP-Clc and alpha-adaptin but not with AP1 and AP3 in S2 cells. Third, neuron-specific depletion of AP2 mimics the dendritic defect in nak mutants and reduction of AP2 gene dose enhances nak-induced dendritic defect. These genetic interactions are specific, as mutations in components of AP1 (AP47SAE-10) and AP3 (garnet1) showed no enhancement of nak-associated dendritic phenotypes (Yang, 2011).

Mutations in Nak DPF motifs that are known to interact with alpha-adaptin (DPF-to-AAA), reducing interaction with AP2, render Nak incapable of rescuing the dendritic defects. As AP2 acts to recruit clathrin to endocytic sites, this functional link between Nak and AP2 implies that the dendritic defect in nak mutants is caused by the disruption of Clathrin-mediated endocytosis (CME). Consistent with this notion, mutations in Chc also interact genetically with nak in dendrite morphogenesis and Nak and clathrin are colocalized in dendrites. Thus, it is suggested that Nak functions through CME to promote dendrite development. Being an Ark family kinase implicated in CME, Nak might function similarly to AAK1 that is known to regulate the activities of clathrin adaptor proteins via phosphorylation in cultured mammalian cells (Conner, 2003; Ricotta, 2002). Consistently, it was shown that Nak kinase activity is indispensable for its ability to rescue dendritic defects. Disrupting dynamin activity in shits1-expressing neurons exhibited stronger defects than nak mutants. In addition to endocytosis, dynamin is known to act in the secretory pathway. Given the known role of the secretory pathway in dendrite morphogenesis, it is possible that only endocytic aspect is disrupted in nak mutants, but both secretory and endocytic aspects are affected in shi mutants (Yang, 2011).

Clathrin- and Nak-positive structures in da neurons are preferentially localized to the branching points of higher-order dendrites. Unlike Rab4, Rab5 and Rab11 that are mobile in dendrites, these clathrin/Nak puncta are stationary. Importantly, it was possible to correlate the localization of these stationary clathrin/Nak puncta with motility of local terminal dendrites. The clathrin puncta in higher-order dendrites probably represent sites where populations of clathrin-coated vesicles actively participate in endocytosis. Consistent with this, these clathrin-positive structures are enriched with PI4,5P2, which is known to assemble endocytic factors functioning in the nucleation of clathrin-coated pits (Mousavi, 2004). The proximity and tight association between localized endocytic machinery and polarized growth have been described in several systems, including the extension of root hair tips, the budding of yeast cells and the navigation of axonal growth cones. Thus, while the mechanism remains to be determined, the requirement of CME in cellular growth appears conserved (Yang, 2011).

How does regionalized endocytosis contribute to dendrite branching? It is proposed that region-specific internalization and recycling of the cell adhesion molecule Nrg is a mechanism for generating local Nrg concentration optimized for higher-order dendrite morphogenesis. In the advance of mammalian axonal growth cones, adherent L1 can provide the tracking force for growth cone extension (Kamiguchi, 2003). As the growth cone advances, L1 is endocytosed in the central region to release unnecessary adhesion and recycled back to the peripheral region. Similarly, continuously recycling of Nrg along the dendritic membrane may help its delivery to growing dendrites that potentially function in promoting dendrite extension or stabilizing newly formed dendrites. Excessive Nrg in higher-order dendrites as in da neurons overexpressing Nrg may inhibit dendrite arborization by generating superfluous adhesion. Thus, Nak-mediated endocytosis could alleviate this inhibition by internalizing Nrg from the cell surface, allowing dendrite elongation (Yang, 2011).

Arborization of higher-order dendrites in Drosophila da neurons requires branching out new dendrites and elongation of existing ones, which requires two other cellular machineries. First, transporting the branch-promoting Rab5-positive organelles to distal dendrites by the microtubule-based dynein transport system is essential for branching activity (Satoh, 2008; Zheng, 2008b). In the absence of Rab5 activity, dendritic branching is largely eliminated and lacking the dynein transport activity limits branching activity to proximal dendrites. Second, the satellite secretory pathway contributes to dendrite growth by mobilizing Golgi outposts to protruding dendrites (Ye, 2007). Similar to Rab proteins, the Golgi outposts labeled by ManII-GFP were only partially colocalized with YFP-Nak and their dendritic distribution is independent of Nak activity. Also, in lva-RNAi larvae in which the transport of Golgi outposts is disrupted (Ye, 2007), YFP-Nak puncta were localized normally to distal dendrites. These findings suggest that localization of Golgi outposts in dendrites is not dependent on Nak activity and localization of YFP-Nak is not dependent on transport of Golgi outposts. It is envisioned that arborization of dendrites is achieved by transporting the branch-promoting factors like Rab5 distally via the dynein transport system. Following the initiation of new branches, dendrite extension requires growth-promoting activity provided by the anterograde Golgi outposts and localized clathrin puncta to promote local growth. To actively distribute clathrin puncta in distal dendrites that are far away from the soma, Nak can participate in the condensation of efficient endocytosis into the punctate structures in higher-order dendrites. It is possible that both stationary Nak/clathrin puncta and secretory Golgi outposts are spatially and temporally coupled to promote extension of dendrites, thus coordinating several events like adhesion to the extracellular matrix, membrane addition/extraction, cargo transport, and cytoskeletal reorganization, eventually building up the sensory tree in the target field (Yang, 2011).

Nak regulates Dlg basal localization in Drosophila salivary gland cells

Protein trafficking is highly regulated in polarized cells. During development, how the trafficking of cell junctional proteins is regulated for cell specialization is largely unknown. In the maturation of Drosophila larval salivary glands (SGs), the Dlg protein is essential for septate junction formation. It was shown that Dlg is enriched in the apical membrane domain of proximal cells and localized basolaterally in distal mature cells. The transition of Dlg distribution is disrupted in nak mutants. Nak associates with the AP-2 subunit alpha-Adaptin and the AP-1 subunit AP-1gamma. In SG cells disrupting AP-1 and AP-2 activities, Dlg is enriched in the apical membrane. Therefore, Nak regulates the transition of Dlg distribution likely through endocytosis of Dlg from the apical membrane domain and transcytosis of Dlg to the basolateral membrane domain during the maturation of SGs development (Peng, 2009).

This study describes the re-localization of the Dlg protein during Drosophila SG specialization. From this analyses, Dlg underwent a transition from the apical to the basal membrane domain. In addition, Nak and components of AP-1 or AP-2 complexes were found to be required for the Dlg transition. Two possible models could explain the transition of Dlg re-localization in SG cells. First, in the proximal SG cells, newly synthesized Dlg is transported to and maintained in the apical membrane. In the distal cells, however, the newly synthesized Dlg is directed toward the basal membrane. Apically deposited Dlg has to be depleted in the transition zone cells, which could be mediated through the endocytic and lysosomal degradative pathway. An alternatively model is that newly synthesized Dlg is targeted to the apical membrane in all SG cells. However, the apical membrane-associated Dlg is re-routed to the basolateral membrane domains, starting in the transition zone cells and continuing in distal cells, via endocytosis and transcytosis. This model could explicitly explain the Dlg mislocalization in the mutants that were analyzed. Due to defects in endocytosis in the AP-2 complex mutants, the Dlg protein is retained in the apical membrane. In AP-1 mutants such as the AP47SHE11/EP1112 transheterozygotes, large Dlg-enriched tubular structures were observed. Similar structures have been reported as specific stages, types, or structures of endosome. Therefore, in the absence of AP-1 activity, failure in vesicle budding from TGN or endosomes may lead to the disruption of targeting Dlg to the basal membrane and Dlg retaining in these organelles. Enrichment of Dlg in apical membrane might be an result inadvertently caused by abnormal intracellular transportation or a pool of Dlg being recycled back to the apical membrane through an AP-1-independent route (Peng, 2009).

In nak mutant SG cells, only the transition of Dlg is defective, but not other polarized proteins, such as aPKC, Syx1A, and Arm. In the severe AP47 and α-ada mutants when Dlg was retained at the apical membrane, the ruffled apical membrane might result from the enriched Dlg protein, leading to excess membrane addition. Such phenotype has been described when Dlg was overexpressed during embryonic cellularization. Therefore, the Dlg transition potentially accounts for the establishment of new septate junctions or basolateral membrane addition during SG cell maturation (Peng, 2009).

Multiple modes of peptide recognition by the PTB domain of the cell fate determinant Numb

The phosphotyrosine-binding (PTB) domain of the cell fate determinant Numb is involved in the formation of multiple protein complexes in vivo and can bind a diverse array of peptide sequences in vitro. To investigate the structural basis for the promiscuous nature of this protein module, its solution structure was determined by NMR in a complex with a peptide containing an NMSF sequence derived from the Numb-associated kinase (Nak). The Nak peptide was found to adopt a significantly different structure from that of a GPpY sequence-containing peptide previously determined. In contrast to the helical turn adopted by the GPpY peptide, the Nak peptide forms a beta-turn at the NMSF site followed by another turn near the C-terminus. The Numb PTB domain appears to recognize peptides that differ in both primary and secondary structures by engaging various amounts of the binding surface of the protein. These results suggest a mechanism through which a single PTB domain might interact with multiple distinct target proteins to control a complex biological process such as asymmetric cell division (Zwahlen, 2000; full text of article).

Numb-associated kinase interacts with the phosphotyrosine binding domain of Numb and antagonizes the function of Numb in vivo

During asymmetric cell division, the membrane-associated Numb protein localizes to a crescent in the mitotic progenitor and is segregated predominantly to one of the two daughter cells. A putative serine/threonine kinase, Numb-associated kinase (Nak), has been identified that interacts physically with the phosphotyrosine binding (PTB) domain of Numb. The PTB domains of Shc and insulin receptor substrate bind to an NPXY motif that is not present in the region of Nak that interacts with Numb PTB domain. The Numb PTB domain but not the Shc PTB domain interacts with Nak through a peptide of 11 amino acids, implicating a novel and specific protein-protein interaction. Overexpression of Nak in the sensory organs causes both daughters of a normally asymmetric cell division to adopt the same cell fate, a transformation similar to the loss of numb function phenotype and opposite the cell fate transformation caused by overexpression of Numb. The frequency of cell fate transformation is sensitive to the numb gene dosage, as expected from the physical interaction between Nak and Numb. These findings indicate that Nak may play a role in cell fate determination during asymmetric cell divisions. The observations made are consistent with the possibility that Nak mediates or modulates the action of asymmetrically distributed Numb. For example, Nak may phosphorylate Numb and negatively regulate Numb function. Alternatively, the interaction of Nak and Numb may prevent the binding of Notch to Numb, thus relieving the inhibition of Notch from Numb. It is also conceivable that Nak may be recruited to the vicinity of Notch due to physical interactions of Numb with Notch and Nak, so that it could phosphorylate Notch or its downstream effectors, thereby inhibiting Notch signaling (Chien, 1998).

Whereas the specific physical interaction between Nak and Numb suggests that Nak may be part of the Numb pathway in specifying daughter cell fate during asymmetric division, it will be necessary to test this possibility by examining both the loss-of-function phenotype and the gain-of-function phenotype of the nak gene. No loss-of-function mutations of the nak gene are currently available. It is worth noting, however, that a number of genes known to be involved in the Numb pathway for asymmetric division exhibit overexpression phenotypes which correspond to cell fate transformations opposite those caused by loss of gene function. Hence, overexpression of the protein products of Delta, Notch,tramtrack, Suppresser of Hairless, orenhancer of split causes transformation of the B cell to the A cell, the hair cell to the socket cell, and the neuron to the sheath cell, opposite their respective loss-of-function phenotypes. Phenotypes due to overexpression of these genes are similar to the numb null mutant phenotype, whereas overexpression of Numb causes the opposite cell fate transformation. The overexpression phenotypes of nak are very similar to those of Notch, tramtrack, and other downstream genes of numb and are therefore highly suggestive of the involvement of nak in asymmetric divisions (Chien, 1998).

The in vivo interaction of Myc-Nak with Numb protein is also indicative of the function of Nak in the asymmetric cell division pathway. In addition to the immunocoprecipitation of Numb and Myc-Nak, it was also observed that the ectopically expressed Myc-Nak localize to the cortical membrane where Numb and Notch are distributed, suggesting that Nak can localize to the site for participation in the asymmetric cell divisions. Due to the overexpression of Myc-Nak, it is difficult to analyze the segregation of Myc-Nak during cell division. Whether Nak is asymmetrically localized during asymmetric cell divisions awaits the availability of an antibody that is suitable for immunocytochemistry (Chien, 1998).

The potential involvement of Nak in asymmetric divisions in Drosophila is reminiscent of the involvement of thepar-1 gene in asymmetric divisions during early embryonic development of C. elegans. Par-1 also contains a serine/threonine kinase domain and a C-terminal region that binds other proteins; whereas the C terminus of Nak binds Numb, the C terminus of Par-1 binds a nonmuscle myosin. A priori, a Numb-binding protein could be involved in asymmetric localization of Numb during asymmetric division or in executing the actions of asymmetrically segregated Numb in specifying daughter cell fate. It appears unlikely that Nak is involved in asymmetric localization of Numb, for the following reasons. First, the Nak overexpression phenotypes could be suppressed by Numb overexpression. This restoration of the proper asymmetric divisions could not have been achieved if overexpression of Nak had abolished asymmetric Numb localization. Second, Nak binds to the PTB domain but not to the rest of the Numb protein. The PTB domain is not necessary for asymmetric localization of Numb in dividing neural precursor cells but is necessary for the ability of Numb to inhibit Notch signaling. Third, both mNumb and mouse Numblike (mNbl; homolog of rNbl) contain PTB domains which are 70 to 75% identical to the PTB domain of dNumb at the amino acid level, and when overexpressed in Drosophila, mNumb and mNbl can transform cell fate in the sensory organ lineages. But only mNumb, not mNbl, is asymmetrically localized in transgenic flies. It thus appears unlikely that Nak plays a role in asymmetric Numb localization (Chien, 1998).

The observation of Nak activity thus far is consistent with the possibility that Nak mediates or modulates the action of asymmetrically distributed Numb. For example, Nak may phosphorylate Numb and negatively regulate Numb function. Alternatively, the interaction of Nak and Numb may prevent the binding of Notch to Numb, thus relieving the inhibition of Notch from Numb. It is also conceivable that Nak may be recruited to the vicinity of Notch due to physical interactions of Numb with Notch and Nak, so that it could phosphorylate Notch or its downstream effectors, thereby inhibiting Notch signaling. These and other possible scenarios may be tested by future genetic and biochemical studies (Chien, 1998).


Search PubMed for articles about Drosophila Nak

Blanpied, T. A., Scott, D. B. and Ehlers, M. D. (2002). Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron 36: 435-449. PubMed ID: 12408846

Chien, C. T., Wang, S., Rothenberg, M., Jan, L. Y. and Jan, Y. N. (1998). Numb-associated kinase interacts with the phosphotyrosine binding domain of Numb and antagonizes the function of Numb in vivo. Mol. Cell Biol. 18(1): 598-607. PubMed ID: 9418906

Conner, S. D. and Schmid, S. L. (2002). Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis. J. Cell Biol. 156: 921-929. PubMed ID: 11877461

Conner, S. D., Schroter, T. and Schmid, S. L. (2003). AAK1-mediated micro2 phosphorylation is stimulated by assembled clathrin. Traffic 4: 885-890. PubMed ID: 14617351

Eisenberg, E. and Greene, L.E. (2007). Multiple roles of auxilin and hsc70 in clathrin-mediated endocytosis. Traffic 8: 640-646. PubMed ID: 17488288

Jan, Y.N. and Jan, L.Y. (2010). Branching out: mechanisms of dendritic arborization. Nat. Rev. Neurosci. 11: 316-328. PubMed ID: 20404840

Jinushi-Nakao, S., et al. (2007). Knot/Collier and Cut control different aspects of dendrite cytoskeleton and synergize to define final arbor shape. Neuron 56: 963-978. PubMed ID: 18093520

Kamiguchi, H. (2003). The mechanism of axon growth: what we have learned from the cell adhesion molecule L1. Mol. Neurobiol. 28: 219-228. PubMed ID: 14709786

Lee, D. W., Zhao, X., Zhang, F., Eisenberg, E. and Greene, L. E. (2005). Depletion of GAK/auxilin 2 inhibits receptor-mediated endocytosis and recruitment of both clathrin and clathrin adaptors. J. Cell Sci. 118: 4311-4321. PubMed ID: 16155256

Mousavi, S. A., Malerød, L., Berg, T. and Kjeken, R. (2004). Clathrin-dependent endocytosis. Biochem. J. 377: 1-16. PubMed ID: 14505490

Peng, Y. H., Yang, W. K., Lin, W. H., Lai, T. T. and Chien, C. T. (2009). Nak regulates Dlg basal localization in Drosophila salivary gland cells. Biochem. Biophys. Res. Commun. 382: 108-113. PubMed ID: 19258011

Ricotta, D., Conner, S. D., Schmid, S. L., von Figura, K. and Honing, S. (2002). Phosphorylation of the AP2 mu subunit by AAK1 mediates high affinity binding to membrane protein sorting signals. J. Cell Biol. 156: 791-795. PubMed ID: 11877457

Satoh, D., et al. (2008). Spatial control of branching within dendritic arbors by dynein-dependent transport of Rab5-endosomes. Nat. Cell Biol. 10(10): 1164-71. PubMed ID: 18758452

Smythe, E. and Ayscough, K.R. (2003). The Ark1/Prk1 family of protein kinases. Regulators of endocytosis and the actin skeleton. EMBO Rep. 4: 246-251. PubMed ID: 12634840

Toshima, J., Toshima, J. Y., Martin, A. C. and Drubin, D. G. (2005). Phosphoregulation of Arp2/3-dependent actin assembly during receptormediated endocytosis. Nat. Cell Biol. 7: 246-254. PubMed ID: 15711538

Yang, W. K., et al. (2011). Nak regulates localization of clathrin sites in higher-order dendrites to promote local dendrite growth. Neuron 72(2): 285-99. PubMed ID: 22017988

Yap, C. C., Wisco, D., Kujala, P., Lasiecka, Z. M., Cannon, J. T., Chang, M. C., Hirling, H., Klumperman, J. and Winckler, B. (2008). The somatodendritic endosomal regulator NEEP21 facilitates axonal targeting of L1/NgCAM. J. Cell Biol. 180: 827-842. PubMed ID: 18299352

Ye, B., Zhang, Y., Song, W., Younger, S. H., Jan, L. Y. and Jan, Y. N. (2007). Growing dendrites and axons differ in their reliance on the secretory pathway. Cell 130: 717-729. PubMed ID: 17719548

Zheng, J., et al. (2008a). Clathrin-dependent endocytosis is required for TrkB-dependent Akt-mediated neuronal protection and dendritic growth. J. Biol. Chem. 283: 13280-13288. PubMed ID: 18353779

Zheng, Y., Wildonger, J., Ye, B., Zhang, Y., Kita, A., Younger, S. H., Zimmerman, S., Jan, L. Y. and Jan, Y. N. (2008b). Dynein is required for polarized dendritic transport and uniform microtubule orientation in axons. Nat. Cell Biol. 10: 1172-1180. PubMed ID: 18758451

Zwahlen, C., Li, S. C., Kay, L. E., Pawson, T. and Forman-Kay, J, D. (2000). Multiple modes of peptide recognition by the PTB domain of the cell fate determinant Numb. EMBO J. 19(7): 1505-15. PubMed ID: 10747019

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date revised: 12 October 2012

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