The neurite outgrowth multiadaptor RhoGAP, NOMA-GAP, regulates neurite extension through SHP2 and Cdc42.
Neuronal differentiation involves the formation and extension of neuronal processes. We have identified a novel regulator of neurite formation and extension, the neurite outgrowth multiadaptor, NOMA-GAP, which belongs to a new family of multiadaptor proteins with RhoGAP activity. We show that NOMA-GAP is essential for NGF-stimulated neuronal differentiation and for the regulation of the ERK5 MAP kinase and the Cdc42 signaling pathways downstream of NGF. NOMA-GAP binds directly to the NGF receptor, TrkA, and becomes tyrosine phosphorylated upon receptor activation, thus enabling recruitment and activation of the tyrosine phosphatase SHP2. Recruitment of SHP2 is required for the stimulation of neuronal process extension and for sustained activation of ERK5 downstream of NOMA-GAP. In addition, we show that NOMA-GAP promotes neurite outgrowth by tempering activation of the Cdc42/PAK signaling pathway in response to NGF. NOMA-GAP, through its dual function as a multiadaptor and RhoGAP protein, thus plays an essential role downstream of NGF in promoting neurite outgrowth and extension.
Max Delbrück Center for Molecular Medicine, Berlin, Germany. m.rosario@mdc-berlin.de
Marta
M
Rosário
Renate
R
Franke
Christien
C
Bednarski
Walter
W
Birchmeier
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D020932:Nerve Growth Factor / Q000378:metabolism; D016501:Neurites / Q000378:metabolism* / Q000648:ultrastructure; D016716:PC12 Cells; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D020798:Two-Hybrid System Techniques; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; D034741:RNA, Small Interfering; C085379:rho GTPase-activating protein; D020932:Nerve Growth Factor; D054462:p21-Activated Kinases; D048054:Mitogen-Activated Protein Kinase 7; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D020764:cdc42 GTP-Binding Protein