Ectodomain shedding of SHPS-1 and its role in regulation of cell migration.
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.
Ohnishi
Hiroshi
H
Biosignal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan.
Kobayashi
Hisae
H
Okazawa
Hideki
H
Ohe
Yoshihide
Y
Tomizawa
Kyoko
K
Sato
Ryuji
R
Matozaki
Takashi
T
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000943:Antigens, Differentiation / Q000737:chemistry* / Q000502:physiology*; D051928:CD47 Antigen; D016466:CHO Cells; D002352:Carrier Proteins / Q000096:biosynthesis; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D003208:Concanavalin A / Q000494:pharmacology; D006224:Cricetinae; D003470:Culture Media; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D039842:Neural Cell Adhesion Molecule L1 / Q000737:chemistry* / Q000502:physiology*; D051419:Paxillin; D010455:Peptides / Q000737:chemistry; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013696:Temperature; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D051928:CD47 Antigen; D002352:Carrier Proteins; C497895:Cd47 protein, mouse; D003470:Culture Media; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; D051419:Paxillin; D010455:Peptides; D010750:Phosphoproteins; C501922:Sirpa protein, mouse; C496062:Pxn protein, mouse; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D003208:Concanavalin A; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D011493:Protein Kinase C; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; D020782:Matrix Metalloproteinases; D018631:ras Proteins