Semaphorin 4D/Plexin-B1 stimulates PTEN activity through R-Ras GTPase-activating protein activity, inducing growth cone collapse in hippocampal neurons.
Plexins are receptors for axonal guidance molecules semaphorins. We recently reported that the semaphorin 4D (Sema4D) receptor, Plexin-B1, suppresses PI3K signaling through the R-Ras GTPase-activating protein (GAP) activity, inducing growth cone collapse. Phosphatidylinositol 3-phosphate level is critically regulated by PI3K and PTEN (phosphatase and tensin homologue deleted chromosome ten). Here we examined the involvement of PTEN in the Plexin-B1-induced repulsive response. Phosphorylation of PTEN at Ser-380 is known to suppress its phosphatase activity. Sema4D induced the dephosphorylation of PTEN at Ser-380 and stimulated PTEN phosphatase activity in hippocampal neurons. Knockdown of endogenous PTEN suppressed the Sema4D-induced growth cone collapse. Phosphorylation mimic PTEN mutant suppressed the Sema4D-induced growth cone collapse, whereas phosphorylation-resistant PTEN mutant by itself induced growth cone collapse. Plexin-B1-induced PTEN dephosphorylation through R-Ras GAP activity and R-Ras GAP activity was by itself sufficient for PTEN dephosphorylation and activation. We also suggested that the Sema4D-induced PTEN dephosphorylation and growth cone collapse were mediated by the inhibition of casein kinase 2 alpha activity. Thus, we propose that Sema4D/Plexin-B1 promotes the dephosphorylation and activation of PTEN through the R-Ras GAP activity, inducing growth cone collapse.
Oinuma
Izumi
I
Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Ito
Yuri
Y
Katoh
Hironori
H
Negishi
Manabu
M
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D019556:COS Cells; D047390:Casein Kinase II / Q000378:metabolism; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D020439:Growth Cones / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism*; D039961:Semaphorins / Q000378:metabolism*; D015398:Signal Transduction; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*
D015703:Antigens, CD; C093224:CD100 antigen; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D011956:Receptors, Cell Surface; D039961:Semaphorins; D020703:ras GTPase-Activating Proteins; D047390:Casein Kinase II; D051059:PTEN Phosphohydrolase