title: The role of Kalirin9 in p75/nogo receptor-mediated RhoA activation in cerebellar granule neurons.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Harrington
authors.forename: Qi Ming
authors.initials: QM
authors.lastname: Li
authors.forename: Chhavy
authors.initials: C
authors.lastname: Tep
authors.forename: Jong Bae
authors.initials: JB
authors.lastname: Park
authors.forename: Zhigang
authors.initials: Z
authors.lastname: He
authors.forename: Sung Ok
authors.initials: SO
authors.lastname: Yoon
mesh_terms: 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*
chemical_list: 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