SH2-B and APS are multimeric adapters that augment TrkA signaling.
Neurotrophins influence growth and survival of sympathetic and sensory neurons through activation of their receptors, Trk receptor tyrosine kinases. Previously, we identified Src homology 2-B (SH2-B) and APS, which are structurally similar adapter proteins, as substrates of Trk kinases. In the present study, we demonstrate that both SH2-B and APS exist in cells as homopentamers and/or heteropentamers, independent of Trk receptor activation. Structure-function analyses revealed that the SH2-B multimerization domain resides within its amino terminus, which is necessary for SH2-B-mediated nerve growth factor (NGF) signaling. Overexpression of SH2-B enhances both the magnitude and duration of TrkA autophosphorylation following exposure of PC12 cells to NGF, and this effect requires the amino-terminal multimerization motif. Moreover, the amino terminus of SH2-B is necessary for TrkA/SH2-B-mediated morphological differentiation of PC12 cells. Together, these results indicate that the multimeric adapters SH2-B and APS influence neurotrophin signaling through direct modulation of Trk receptor autophosphorylation.
Howard Hughes Medical Institute and the Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
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D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002352:Carrier Proteins; D002454:Cell Differentiation; D002460:Cell Line; D002847:Chromatography, Agarose; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D017353:Gene Deletion; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008957:Models, Genetic; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C518910:SH2B1 protein, human; C492010:SH2B1 protein, rat; C107249:SH2B2 protein, human; C488161:Sh2b2 protein, mouse; C488162:Sh2b2 protein, rat; D020932:Nerve Growth Factor; D020917:Receptor, trkA