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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cell Line
-
Cerebellum / cytology
-
Cerebellum / metabolism*
-
GPI-Linked Proteins
-
Guanine Nucleotide Dissociation Inhibitors / metabolism
-
Guanine Nucleotide Exchange Factors / metabolism*
-
Myelin Proteins
-
Myelin-Associated Glycoprotein / metabolism
-
Nerve Tissue Proteins
-
Neurites / metabolism*
-
Nogo Receptor 1
-
Protein Structure, Secondary / physiology
-
Protein Structure, Tertiary / physiology
-
Rats
-
Receptors, Cell Surface
-
Receptors, Growth Factor
-
Receptors, Nerve Growth Factor / metabolism*
-
Receptors, Peptide / metabolism*
-
Rho Guanine Nucleotide Exchange Factors
-
rho-Specific Guanine Nucleotide Dissociation Inhibitors
-
rhoA GTP-Binding Protein / metabolism*
Substances
-
GPI-Linked Proteins
-
Guanine Nucleotide Dissociation Inhibitors
-
Guanine Nucleotide Exchange Factors
-
Kalrn protein, rat
-
Myelin Proteins
-
Myelin-Associated Glycoprotein
-
Nerve Tissue Proteins
-
Nogo Receptor 1
-
Receptors, Cell Surface
-
Receptors, Growth Factor
-
Receptors, Nerve Growth Factor
-
Receptors, Peptide
-
Rho Guanine Nucleotide Exchange Factors
-
Rtn4r protein, rat
-
rho-Specific Guanine Nucleotide Dissociation Inhibitors
-
Ngfr protein, rat
-
rhoA GTP-Binding Protein