The role of Kalirin9 in p75/nogo receptor-mediated RhoA activation in cerebellar granule neurons.
p75 and the Nogo receptor form a signaling unit for myelin inhibitory molecules, with p75 being responsible for RhoA activation. Because p75 lacks the GDP/GTP exchange factor domain, it has remained unclear how p75 activates RhoA. Here, we report that Kalirin9, a dual RhoGEF, binds p75 directly and regulates p75-Nogo receptor-dependent RhoA activation and neurite inhibition in response to myelin-associated glycoprotein. The region of p75 that Kalirin9 binds includes its mastoparan-like fifth helix, which was shown to recruit RhoGDI-RhoA. As predicted from the presence of a shared binding site, we found that Kalirin9 competes with RhoGDI for p75 binding in a dose-dependent manner in vitro. In line with these data, myelin-associated glycoprotein addition to cerebellar granule neurons resulted in a reduction in the association of Kalirin9 with p75, and a simultaneous increase in the binding of RhoGDI to p75. These results reveal a mechanism by which the fifth helix of p75 regulates RhoA activation.
Harrington
Anthony W
AW
Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, The Ohio State University, Columbus, Ohio 43210, USA.
Li
Qi Ming
QM
Tep
Chhavy
C
Park
Jong Bae
JB
He
Zhigang
Z
Yoon
Sung Ok
SO
D000818:Animals; D002460:Cell Line; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D058851:GPI-Linked Proteins; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009419:Nerve Tissue Proteins; D016501:Neurites / Q000378:metabolism*; D000070816:Nogo Receptor 1; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D058851:GPI-Linked Proteins; D020730:Guanine Nucleotide Dissociation Inhibitors; D020662:Guanine Nucleotide Exchange Factors; C102365:Kalrn protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D009419:Nerve Tissue Proteins; D000070816:Nogo Receptor 1; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D018000:Receptors, Peptide; D064067:Rho Guanine Nucleotide Exchange Factors; C486581:Rtn4r protein, rat; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; C068313:Ngfr protein, rat; D020742:rhoA GTP-Binding Protein