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J. Biol. Chem. 279 (27): 27878-27887

© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

Ectodomain Shedding of SHPS-1 and Its Role in Regulation of Cell Migration*

Hiroshi Ohnishi, Hisae Kobayashi, Hideki Okazawa, Yoshihide Ohe, Kyoko Tomizawa, Ryuji Sato, , and Takashi Matozaki{ddagger}

Biosignal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan

Abstract: SHPS-1 is a transmembrane protein whose cytoplasmic region undergoes tyrosine phosphorylation and then binds the protein-tyrosine phosphatase SHP-2. Formation of the SHPS-1-SHP-2 complex is implicated in regulation of cell migration. In addition, SHPS-1 and its ligand CD47 constitute an intercellular recognition system that contributes to inhibition of cell migration by cell-cell contact. The ectodomain of SHPS-1 has now been shown to be shed from cells in a reaction likely mediated by a metalloproteinase. This process was promoted by activation of protein kinase C or of Ras, and the released ectodomain exhibited minimal CD47-binding activity. Metalloproteinases catalyzed the cleavage of a recombinant SHPS-1-Fc fusion protein in vitro, and the primary cleavage site was localized to the juxtamembrane region of SHPS-1. Forced expression of an SHPS-1 mutant resistant to ectodomain shedding impaired cell migration, cell spreading, and reorganization of the actin cytoskeleton. It also increased the tyrosine phosphorylation of paxillin and FAK triggered by cell adhesion. These results suggest that shedding of the ectodomain of SHPS-1 plays an important role in regulation of cell migration and spreading by this protein.

Received for publication December 1, 2003. Revision received March 29, 2004.

{ddagger} To whom correspondence should be addressed. Tel.: 81-27-220-8865; Fax: 81-27-220-8897; E-mail: matozaki{at}

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