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Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, activate Trk receptor tyrosine kinases through receptor dimerization at the cell surface followed by autophosphorylation and recruitment of intracellular signaling molecules. The intracellular pathways used by neurotrophins share many common protein substrates that are used by other receptor tyrosine kinases (RTK), such as Shc, Grb2, FRS2, and phospholipase C-γ. Here we describe a novel RTK mechanism that involves a 220-kilodalton membrane tetraspanning protein, ARMS/Kidins220, which is rapidly tyrosine phosphorylated in primary neurons after neurotrophin treatment. ARMS/Kidins220 undergoes multiple tyrosine phosphorylation events and also serine phosphorylation by protein kinase D. We have identified a single tyrosine (Tyr1096) phosphorylation event in ARMS/Kidins220 that plays a critical role in neurotrophin signaling. A reassembled complex of ARMS/Kidins220 and CrkL, an upstream component of the C3G-Rap1-MAP kinase cascade, is SH3-dependent. However, Tyr1096 phosphorylation enables ARMS/Kidins220 to recruit CrkL through its SH2 domain, thereby freeing the CrkL SH3 domain to engage C3G for MAP kinase activation in a neurotrophin dependent manner. Accordingly, mutation of Tyr1096 abolished CrkL interaction and sustained MAPK kinase activity, a response that is not normally observed in other RTKs. Therefore, Trk receptor signaling involves an inducible switch mechanism through an unconventional substrate that distinguishes neurotrophin action from other growth factor receptors. Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, activate Trk receptor tyrosine kinases through receptor dimerization at the cell surface followed by autophosphorylation and recruitment of intracellular signaling molecules. The intracellular pathways used by neurotrophins share many common protein substrates that are used by other receptor tyrosine kinases (RTK), such as Shc, Grb2, FRS2, and phospholipase C-γ. Here we describe a novel RTK mechanism that involves a 220-kilodalton membrane tetraspanning protein, ARMS/Kidins220, which is rapidly tyrosine phosphorylated in primary neurons after neurotrophin treatment. ARMS/Kidins220 undergoes multiple tyrosine phosphorylation events and also serine phosphorylation by protein kinase D. We have identified a single tyrosine (Tyr1096) phosphorylation event in ARMS/Kidins220 that plays a critical role in neurotrophin signaling. A reassembled complex of ARMS/Kidins220 and CrkL, an upstream component of the C3G-Rap1-MAP kinase cascade, is SH3-dependent. However, Tyr1096 phosphorylation enables ARMS/Kidins220 to recruit CrkL through its SH2 domain, thereby freeing the CrkL SH3 domain to engage C3G for MAP kinase activation in a neurotrophin dependent manner. Accordingly, mutation of Tyr1096 abolished CrkL interaction and sustained MAPK kinase activity, a response that is not normally observed in other RTKs. Therefore, Trk receptor signaling involves an inducible switch mechanism through an unconventional substrate that distinguishes neurotrophin action from other growth factor receptors. Neurotrophins are a family of growth factors that exert their action through the Trk receptor tyrosine kinases and the p75 neurotrophic receptor (p75NTR). All neurotrophins bind to p75NTR, but nerve growth factor (NGF) 4The abbreviations used are: NGFnerve growth factorBDNFbrain-derived neurotrophic factorTricineN-2-hydroxy-1,1-bis(hydroxymethyl)ethylglycineGSTglutathione S-transferase. binds specifically to TrkA, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) bind to TrkB, and neurotrophin-3 (NT-3) binds preferentially to TrkC (1Chao M.V. Nat. Rev. Neurosci. 2003; 4: 299-309Crossref PubMed Scopus (1768) Google Scholar, 2Huang E.J. Reichardt L.F. Annu. Rev. Biochem. 2003; 72: 609-642Crossref PubMed Scopus (1982) Google Scholar). Signaling mediated by neurotrophins produces several effects in the nervous system including survival of peripheral neurons during embryonic development and promotion of axonal growth and branching as well as modulation of synaptic activity (1Chao M.V. Nat. Rev. Neurosci. 2003; 4: 299-309Crossref PubMed Scopus (1768) Google Scholar, 2Huang E.J. Reichardt L.F. Annu. Rev. Biochem. 2003; 72: 609-642Crossref PubMed Scopus (1982) Google Scholar, 3Poo M.M. Nat. Rev. Neurosci. 2001; 2: 24-32Crossref PubMed Scopus (1532) Google Scholar). nerve growth factor brain-derived neurotrophic factor N-2-hydroxy-1,1-bis(hydroxymethyl)ethylglycine glutathione S-transferase. Like other receptor tyrosine kinases, Trk receptors are activated after ligand-induced dimerization. Upon neurotrophin binding, activated Trk receptors provide several docking sites for different adaptor proteins and enzymes. Two tyrosine residues, Tyr490 and Tyr785, are principally responsible for triggering the majority of the different intracellular signaling pathways for neurotrophins. Phosphorylation of Tyr490 site is responsible for initiating MAPK and phosphatidylinositol 3-kinase/Akt activities, whereas the Tyr785 site engages phospholipase C-γ and protein kinase C activities (1Chao M.V. Nat. Rev. Neurosci. 2003; 4: 299-309Crossref PubMed Scopus (1768) Google Scholar, 2Huang E.J. Reichardt L.F. Annu. Rev. Biochem. 2003; 72: 609-642Crossref PubMed Scopus (1982) Google Scholar). These activities are promoted by a set of adaptor proteins, such as Shc, Grb2, Gab1, and FRS2. Two of these proteins, Shc and FRS2, interact directly with phosphorylated tyrosine residue Tyr490 (4Meakin S.O. MacDonald J.I. Gryz E.A. Kubu C.J. Verdi J.M. J. Biol. Chem. 1999; 274: 9861-9870Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 5Kao S. Jaiswal R.K. Kolch W. Landreth G.E. J. Biol. Chem. 2001; 276: 18169-18177Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar). However, several reports suggest that the Shc-binding Tyr490 site does not fully account for the survival and differentiation activities associated with neurotrophin action. Mice harboring Y490F mutations in TrkB and TrkC receptors display only minimal neurotrophin-related deficits (6Minichiello L. Casagranda F. Tatche R.S. Stucky C.L. Postigo A. Lewin G.R. Davies A.M. Klein R. Neuron. 1998; 21: 335-345Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 7Postigo A. Calella A.M. Fritzsch B. Knipper M. Katz D. Eilers A. Schimmang T. Lewin G.R. Klein R. Minichiello L. Genes Dev. 2002; 16: 633-645Crossref PubMed Scopus (75) Google Scholar), in contrast to mice lacking Trk tyrosine kinase activity entirely (8Klein R. Silos-Santiago I. Smeyne R.J. Lira S.A. Brambilla R. Bryant S. Zhang L. Snider W.D. Barbacid M. Nature. 1994; 368: 249-251Crossref PubMed Scopus (537) Google Scholar, 9Klein R. Smeyne R.J. Wurst W. Long L.K. Auerbach B.A. Joyner A.L. Barbacid M. Cell. 1993; 75: 113-122Abstract Full Text PDF PubMed Scopus (585) Google Scholar, 10Smeyne R.J. Klein R. Schnapp A. Long L.K. Bryant S. Lewin A. Lira S.A. Barbacid M. Nature. 1994; 368: 246-249Crossref PubMed Scopus (843) Google Scholar), which display significant losses of peripheral neurons during development. Hence, there are other Tyr490-independent mechanisms that also account for the effects of neurotrophins. One recently reported Trk-associated molecule, the ankyrin-rich membrane-spanning (ARMS/Kidins220) protein (referred hereafter as ARMS), represents a prime candidate for a specific target of Trk receptor tyrosine phosphorylation (11Kong H. Boulter J. Weber J.L. Lai C. Chao M.V. J. Neurosci. 2001; 21: 176-185Crossref PubMed Google Scholar). ARMS is a transmembrane protein highly expressed in many Trk receptor neuronal populations. The ARMS protein is closely associated with Trk receptors through its transmembrane domains but does not interact with the epidermal growth factor receptor (12Arevalo J.C. Yano H. Teng K.K. Chao M.V. EMBO J. 2004; 23: 2358-2368Crossref PubMed Scopus (110) Google Scholar). ARMS is a large protein that contains a SAM domain, mutiple potential phosphorylation sites (>40), and a PDZ-binding motif at the C terminus. It does not contain classical domains of adaptor proteins, such as SH2, SH3, or pleckstrin homology (PH) domains. Recently, ARMS has been shown to be phosphorylated after neurotrophin treatment in PC12 cells and cortical neurons, leading to a prolonged MAP kinase response (12Arevalo J.C. Yano H. Teng K.K. Chao M.V. EMBO J. 2004; 23: 2358-2368Crossref PubMed Scopus (110) Google Scholar). It also serves as a substrate for protein kinase D (13Iglesias T. Cabrera-Poch N. Mitchell M.P. Naven T.J. Rozengurt E. Schiavo G. J. Biol. Chem. 2000; 275: 40048-40056Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Here we demonstrate a new mechanism for receptor tyrosine kinases that involves the phosphorylation of ARMS at a single tyrosine residue to produce a switch between short term and long term signaling. Mutation of this amino acid impairs prolonged MAPK activation and differentiation of PC12 cells in response to NGF treatment. Our data support a model in which a constitutive association of Trk receptors, ARMS and CrkL, is altered by a switch in the motif recognition of adaptor molecules after neurotrophin treatment. The phosphorylation of a specific tyrosine residue in ARMS allows the adaptor protein CrkL to engage C3G and activate Rap1. These results provide a new mechanism that goes beyond established models of neurotrophin signaling (1Chao M.V. Nat. Rev. Neurosci. 2003; 4: 299-309Crossref PubMed Scopus (1768) Google Scholar, 2Huang E.J. Reichardt L.F. Annu. Rev. Biochem. 2003; 72: 609-642Crossref PubMed Scopus (1982) Google Scholar, 14Segal R.A. Greenberg M.E. Annu. Rev. Neurosci. 1996; 19: 463-489Crossref PubMed Scopus (908) Google Scholar, 15Kaplan D.R. Miller F.D. Curr. Opin. Neurobiol. 2000; 10: 381-391Crossref PubMed Scopus (1670) Google Scholar) and indicate that Trk receptor tyrosine phosphorylation is capable of altering its signaling potential through a non-conventional downstream substrate. Subcellular Fractionation—Subcellular fractionation was performed as described previously (16Yano H. Chao M.V. J. Neurobiol. 2004; 58: 244-257Crossref PubMed Scopus (59) Google Scholar), using iodixanol density gradient centrifugation. Cortical neurons (DIV11) were homogenized using a Dounce homogenizer in buffer H (250 mm sucrose, 20 mm Tricine-NaOH, pH 7.8, 1 mm EDTA, 2 mm MgCl2, with protease and phosphatase inhibitors). Membrane fractions (P2 and P3) were prepared by sequential centrifugation (800, 16,000, and 200,000 × g). P2 was then adjusted to 25% iodixanol (OptiPrep; Accurate, Westbury, NY) and overlaid with 20, 15, 10, and 5% iodixanol in buffer H. Gradients were centrifuged either in a SW40Ti rotor (Beckman, Fullerton, CA) at 27,000 rpm for 18 h or in a TLS55 rotor (Beckman) at 38,000 rpm for 5 h at 4°C. After gradient centrifugation, membrane fractions were collected, and equal volumes were analyzed by SDS-PAGE and immunoblotting with different antibodies. Preparation of GST Fusion Proteins and in Vitro Binding Assays—For the production of tyrosine-phosphorylated recombinant proteins, TKX1 bacteria (Stratagene) were used. We followed the instructions recommended by the manufacturer. Briefly, expression of recombinant proteins in TKX1 bacteria was induced with 0.1 mm isopropyl β-d-thiogalactopyranoside for 2 h at 37°C. After collecting the cells the expression of the tyrosine kinase gene was induced in tryptophan starvation media containing indoleacrylic acid, and 2 h later bacteria were harvested, and recombinant tyrosine-phosphorylated GST fusion proteins were purified. In vitro binding experiments were performed as described previously (12Arevalo J.C. Yano H. Teng K.K. Chao M.V. EMBO J. 2004; 23: 2358-2368Crossref PubMed Scopus (110) Google Scholar). In Vitro Protein Translation—The wild type, R39N and W160L CrkL constructs, were in vitro translated and 35S-labeled with the TNT-coupled reticulocyte lysate system using pDual GC vector (Promega, Madison, WI). Following translation, 35S-labeled CrkL proteins were incubated with HEK293 cell extracts in 1% Nonidet P-40 lysis buffer at 4 °C for 7 h with GST alone or GST-ARMS tyrosine-phosphorylated or non-tyrosine-phosphorylated recombinant proteins prebound to glutathione-Sepharose beads (Amersham Biosciences). The beads were then washed with lysis buffer and boiled in 1xLaemmli sample buffer. Proteins were resolved by SDS-PAGE, and 35S-labeled proteins were visualized by autoradiography with signal enhancement (Amplify, Amersham Biosciences). Levels of GST fusion proteins were assessed by Coomassie Blue RC50 staining (Amersham Biosciences). Generation and Affinity Purification of Antibodies against Phosphorylated containing phosphorylated Tyr1096 of ARMS protein was used to The of against the phosphorylated residue was as described previously R. Chao M.V. J. Neurosci. 2004; PubMed Scopus Google Scholar). was of using an by the of the to beads (Amersham Biosciences). The from the was then through a by the to The was washed with containing 20, and were then with 0.1 pH were from the with pH and then for by ARMS from neurotrophin of to as we used a to that described previously J. A. Klein R. Neuron. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), with Briefly, cortical primary were in mm mm pH and 5 mm with were to for at 4 The were the of a density gradient by to in a of containing and were After centrifugation at rpm for fractions were from the volumes of were analyzed by ARMS at Tyr1096 in to is phosphorylated many tyrosine in response to neurotrophins (11Kong H. Boulter J. Weber J.L. Lai C. Chao M.V. J. Neurosci. 2001; 21: 176-185Crossref PubMed Google Scholar, J.C. Yano H. Teng K.K. Chao M.V. EMBO J. 2004; 23: 2358-2368Crossref PubMed Scopus (110) Google Scholar). However, specific tyrosine have been in the ARMS We the amino acid of ARMS to for tyrosine One was in the of ARMS that to the previously described for binding to the SH2 domain of CrkL a 2001; PubMed Scopus Google CrkL was previously to interact through its SH3 domain with a of ARMS (12Arevalo J.C. Yano H. Teng K.K. Chao M.V. EMBO J. 2004; 23: 2358-2368Crossref PubMed Scopus (110) Google Scholar). ARMS undergoes tyrosine phosphorylation at we against a this phosphorylated PC12 cells and cortical neurons were with NGF and ARMS protein was with an and to with the in the of phosphorylated ARMS protein was observed NGF treatment in PC12 cells and treatment of cortical neurons These results that the Tyr1096 residue in ARMS was phosphorylated neurotrophin treatment. the of the we HEK293 cells with wild ARMS and with activation in a signal by the of wild ARMS with However, with a a in the tyrosine phosphorylation in These results that the for phosphorylated ARMS to SH2 of the of the in we recombinant tyrosine-phosphorylated GST fusion proteins ARMS The recombinant proteins were phosphorylated tyrosine using the which contains an inducible tyrosine kinase activity The proteins were and used to protein interaction The GST fusion proteins were analyzed for their to bind to CrkL, a binding of ARMS (12Arevalo J.C. Yano H. Teng K.K. Chao M.V. EMBO J. 2004; 23: 2358-2368Crossref PubMed Scopus (110) Google Scholar). The tyrosine-phosphorylated protein CrkL protein with the protein and between the binding of to the SH2 and the SH3 domains of CrkL, a of the was analyzed an association between CrkL and tyrosine-phosphorylated protein was whereas the interaction not the was not tyrosine-phosphorylated 5 and that ARMS bind to the SH2 domain of CrkL through a residue of this the Tyr1096 was to The interaction between the GST-ARMS proteins and CrkL was abolished Binding to CrkL was not with the tyrosine-phosphorylated proteins and that not contain the Tyr1096 the for this tyrosine and the interaction between phosphorylated and CrkL was also by mutation of Tyr1096 These results suggest that constitutive binding of the SH3 domain of CrkL to ARMS also this tyrosine residue for The of amino of the motif in protein has been previously reported a 2001; PubMed Scopus Google Scholar). between ARMS and were not using recombinant proteins not These indicate that the binding of ARMS to CrkL be by the phosphorylation of ARMS specifically at the of SH2 domain of CrkL in interaction CrkL proteins were and for association with In vitro translated wild CrkL with GST-ARMS fusion proteins A SH2 CrkL protein, that abolished the interaction with as or C. B. C.L. Cell. Biol. 1998; PubMed Scopus Google Scholar), was not capable of binding to tyrosine-phosphorylated GST-ARMS the other an SH3 CrkL that the binding of or C3G C. B. C.L. Cell. Biol. 1998; PubMed Scopus Google Scholar), not display constitutive association but the interaction with phosphorylated GST-ARMS proteins a binding of not display binding to the CrkL These data support an interaction of the ARMS and CrkL proteins mediated by the phosphorylation of ARMS at residue Tyr1096 and the SH2 domain of Trk CrkL, and in the association of CrkL, and Trk receptors we gradient centrifugation of from primary cortical the in as with using cell The gradient intracellular membrane including and (16Yano H. Chao M.V. J. Neurobiol. 2004; 58: 244-257Crossref PubMed Scopus (59) Google Scholar). Membrane fractions were prepared by sequential centrifugation and then adjusted to 25% The P2 was to gradient centrifugation from were then to SDS-PAGE and for Trk and After centrifugation, CrkL, and were in the fractions as an of ARMS and using also these CrkL, and were not in the or as assessed by and Trk receptors were in but a with of these primary neurons in a of Trk receptors to the of the other proteins in these fractions results have been observed in the of and ARMS in cells H. Chao M.V. PubMed Scopus Google Scholar). These data suggest that CrkL, and in membrane as a for the of signaling for a of and their receptors, including growth S. A. S. J. Biol. 2002; PubMed Scopus Google Scholar) and epidermal growth factor S. Cell. Biol. 2002; PubMed Scopus Google Scholar). be with experiments that Trk and ARMS in a complex to its activation (12Arevalo J.C. Yano H. Teng K.K. Chao M.V. EMBO J. 2004; 23: 2358-2368Crossref PubMed Scopus (110) Google Scholar, J.C. Chao M.V. J. Neurosci. 2004; PubMed Scopus Google Scholar) in J. J. Neurosci. 1996; 16: PubMed Google Scholar). membrane in cell signaling are a T. S. Curr. Opin. Neurobiol. 2004; PubMed Scopus Google Scholar). has been reported that Trk receptors are to in response to neurotrophins in cortical neurons S. T. H. T. H. L. B. M. J. Biol. 2004; PubMed Scopus Google Scholar). ARMS and CrkL are in these we from primary cortical neurons in or of treatment using and centrifugation in an ARMS and TrkB are in the CrkL in that are and we not an of this protein in as with fractions as is for TrkB and induced the of a of TrkB receptors to the of ARMS and CrkL and receptor were used as and for association MAPK and in PC12 effects of factors that are long from the nerve to the cell It has been that signaling containing the receptor and associated proteins are to the cell are to effects and differentiation J. J. Neurosci. 1996; 16: PubMed Google Scholar). phosphorylation of ARMS at Tyr1096 is directly in neurotrophin we assessed the of NGF to signal through the Trk A well established response is the of MAP kinase Therefore, PC12 cells were with and and the activation of MAP kinase was followed in response to Our results that the activation of MAP kinase was with the with the wild ARMS or alone be observed the staining at 5 of NGF treatment effects were observed in MAPK activation at 5 after NGF treatment We also a in the of PC12 cells with that in with and cells A in the of cells was observed These data support the of ARMS tyrosine phosphorylation at Tyr1096 residue in sustained MAPK activation and in the of PC12 cells by neurotrophins. It was previously reported that C3G binding to CrkL with neurotrophin treatment (12Arevalo J.C. Yano H. Teng K.K. Chao M.V. EMBO J. 2004; 23: 2358-2368Crossref PubMed Scopus (110) Google Scholar). the Tyr1096 residue in ARMS was for this we performed in vitro binding with GST-ARMS fusion In contrast to ARMS protein a in binding of C3G to CrkL was observed with fusion protein of the of C3G that there was binding in the of wild ARMS the of ARMS that the These results that the Tyr1096 residue of ARMS is for the association of C3G to signal through Trk receptor tyrosine kinases is well (1Chao M.V. Nat. Rev. Neurosci. 2003; 4: 299-309Crossref PubMed Scopus (1768) Google Scholar, 2Huang E.J. Reichardt L.F. Annu. Rev. Biochem. 2003; 72: 609-642Crossref PubMed Scopus (1982) Google Scholar, 15Kaplan D.R. Miller F.D. Curr. Opin. Neurobiol. 2000; 10: 381-391Crossref PubMed Scopus (1670) Google Scholar), in from the between other receptor tyrosine kinases to Trk receptors. A common set of proteins is to receptor tyrosine the of Trk receptor is the activation of phospholipase MAP kinase and phosphatidylinositol activities, which are by of the RTK Here we describe an protein substrate for neurotrophin receptors, the ARMS protein, which is a large protein with closely transmembrane domains. this of protein has not been observed in other tyrosine kinase for activation of protein, is a single transmembrane protein that is by the cell receptor in C.L. R.K. A. Zhang W. J. 2001; PubMed Scopus Google Scholar). potential phosphorylation we have identified a tyrosine phosphorylation event in ARMS protein that serves to recruit CrkL through its SH2 In vitro binding established that this interaction is of a the for the SH3 domain of CrkL of this phosphorylation event impairs the prolonged MAPK activation and the of PC12 cells in response to neurotrophins 5 and is the of binding between ARMS and is an the Tyr1096 is amino of the in ARMS used to bind the CrkL SH3 A model be in which a constitutive association of through the in ARMS and SH3 domain of of Trk receptors by neurotrophins the phosphorylation of the Tyr1096 residue in ARMS that binds to the SH2 domain of switch in the binding for the of the SH3 domain of CrkL to recruit C3G and the activation of MAPK the of signal be by a constitutive interaction of ARMS and CrkL for an of MAP kinase ARMS tyrosine-phosphorylated for this model from that C3G recruitment is to the complex phosphorylation (12Arevalo J.C. Yano H. Teng K.K. Chao M.V. EMBO J. 2004; 23: 2358-2368Crossref PubMed Scopus (110) Google Scholar). A complex has also been observed in experiments (11Kong H. Boulter J. Weber J.L. Lai C. Chao M.V. J. Neurosci. 2001; 21: 176-185Crossref PubMed Google Scholar, J.C. Yano H. Teng K.K. Chao M.V. EMBO J. 2004; 23: 2358-2368Crossref PubMed Scopus (110) Google Scholar, J.C. Chao M.V. J. Neurosci. 2004; PubMed Scopus Google Scholar). that in proteins that the binding of to other signaling proteins M. J. Teng K.K. J.I. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, N. H. A. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. 2001; PubMed Scopus Google Scholar). is that tyrosine-phosphorylated ARMS CrkL to its SH3 domain for recruitment of C3G or other adaptor adaptor proteins and 2001; PubMed Scopus Google Scholar). Therefore, of neurotrophin signaling be dependent the specific phosphorylation of ARMS and the expression of other signaling In this the Tyr1096 residue was to be critical for the activation of a signaling MAP of phosphorylation in ARMS abolished CrkL interaction and prolonged MAPK activation and differentiation of PC12 cells in response to neurotrophins 5 and The switch in domain for is directly by the binding and phosphorylation of ARMS and CrkL and in neurotrophin signaling is the intracellular of Trk receptors and their of in PC12 cells to its and in C. Lai J. Neurosci. 2001; 21: PubMed Google Scholar). It has been that activated Trk receptors signal during the after H. H. J. J. C. Chao M.V. J. Neurosci. 2001; 21: PubMed Google Scholar, C. Neuron. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, H. R. Neuron. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) and in intracellular such as the R. Chao M.V. J. Neurosci. 2004; PubMed Scopus Google Scholar). We have the CrkL, and proteins in the membrane as Trk receptors with a for The of ARMS with is with the of in C. Lai J. Neurosci. 2001; 21: PubMed Google Scholar). with a ARMS has been also associated in in neurons N. L. M. T. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), TrkB receptors have been to be in response to neurotrophins S. T. H. T. H. L. B. M. J. Biol. 2004; PubMed Scopus Google Scholar). are in in density such as and in many signaling at the cell surface a T. S. Curr. Opin. Neurobiol. 2004; PubMed Scopus Google Scholar). It is to that the of ARMS in has a role in the neurotrophin signaling after recruitment of Trk receptors to these The ARMS protein is a of an family of and with a as of the of signaling L. Biol. 2004; PubMed Google Scholar). It be that ARMS as a substrate for tyrosine phosphorylation (11Kong H. Boulter J. Weber J.L. Lai C. Chao M.V. J. Neurosci. 2001; 21: 176-185Crossref PubMed Google Scholar). In experiments indicate that ARMS/Kidins220 interact with and signaling S. Lai J.C. M.E. Chao M.V. J. Cell. Biol. PubMed Scopus Google Scholar). The of ARMS in signal has to be fully but is to a role in the response to We the of the Chao and for for and for
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