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J. Biol. Chem., Vol. 276, Issue 18, 15216-15224, May 4, 2001
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From the Second Department of Internal Medicine, Kobe University
School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
and § Biosignal Research Center, Institute for Molecular and
Cellular Regulation, Gunma University, 3-39-15 Showa-Machi,
Maebashi 371-8512, Japan
SAP-1 (stomach cancer-associated
protein-tyrosine phosphatase-1) is a transmembrane-type
protein-tyrosine phosphatase that is abundant in the brain and certain
cancer cell lines. With the use of a "substrate-trapping" approach,
p130cas, a major focal adhesion-associated phosphotyrosyl
protein, has now been identified as a likely physiological substrate of
SAP-1. Expression of recombinant SAP-1 induced the dephosphorylation of
p130cas as well as that of two other components of the
integrin-signaling pathway (focal adhesion kinase and p62dok)
in intact cells. In contrast, expression of a substrate-trapping mutant
of SAP-1 induced the hyperphosphorylation of these proteins, indicating
a dominant negative effect of this mutant. Overexpression of SAP-1
induced disruption of the actin-based cytoskeleton as well as inhibited
various cellular responses promoted by integrin-mediated cell adhesion,
including cell spreading on fibronectin, growth factor-induced
activation of extracellular signal-regulated kinase 2, and colony
formation. Finally, the enzymatic activity of SAP-1, measured with an
immunocomplex phosphatase assay, was substantially increased by
cell-cell adhesion. These results suggest that SAP-1, by mediating the
dephosphorylation of focal adhesion-associated substrates, negatively
regulates integrin-promoted signaling processes and, thus, may
contribute to contact inhibition of cell growth and motility.
Inhibition of Cell Growth and Spreading by Stomach
Cancer-associated Protein-tyrosine Phosphatase-1 (SAP-1) through
Dephosphorylation of p130cas*
,
*
This study was supported by a grant-in-aid for cancer
research and a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan and by a
grant-in-aid for research for the Future Program from the Japan Society
for the Promotion of Science.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 81-78-382-5861;
Fax: 81-78-382-2080; E-mail: noguchi@med.kobe-u.ac.jp.
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