Protein tyrosine phosphatase SHP2 is involved in Semaphorin 4D-induced axon repulsion.
Semaphorin-4D (Sema4D), a member of class 4 membrane-bound Semaphorins, acts as a chemorepellant to the axons of retinal ganglion cells and hippocampal neurons. Plexin-B1, a neuronal Sema4D receptor, associates with either one of receptor tyrosine kinases, c-Met or ErbB2, to mediate Sema4D-signaling. In contrast to this significance, the involvement of protein tyrosine phosphatases in Semaphorin-signaling remains unknown. We here show that Src homology 2-containing protein-tyrosine phosphatase 2 (SHP2) participates in Sema4D-signaling. SHP2 was localized in the growth cones of chick embryonic retinal ganglion neurons. Phenylarsine oxide, a protein tyrosine phosphatase inhibitor, suppressed Sema4D-induced contractile response in COS-7 cells expressing Plexin-B1. Ectopic expression of a phosphatase-inactive mutant of SHP2 in the retinal ganglion cells attenuated Sema4D-induced growth cone collapse response. A SHP1/2 specific inhibitor, 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), also suppressed this collapse response. These results suggest that SHP2-mediated tyrosine dephosphorylation is an important step in Sema4D-induced axon repulsion.
Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Taro
T
Fuchikawa
Fumio
F
Nakamura
Nana
N
Fukuda
Kohtaro
K
Takei
Yoshio
Y
Goshima
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D019556:COS Cells; D002645:Chickens; D002522:Chlorocebus aethiops; D020439:Growth Cones / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D055495:Neurogenesis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000502:physiology*; D039961:Semaphorins / Q000378:metabolism*
D015703:Antigens, CD; C093224:CD100 antigen; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D011956:Receptors, Cell Surface; D039961:Semaphorins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11