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J Biol Chem, Vol. 273, Issue 48, 31890-31900, November 27, 1998
From the The roles of protein-tyrosine phosphatases (PTPs)
in processes such as cell growth and adhesion are poorly understood. To explore the ability of specific PTPs to regulate cell signaling pathways initiated by stimulation of growth factor receptors, we
expressed the receptor-like PTP, PTP
Protein-tyrosine Phosphatase
Regulates Src Family Kinases and
Alters Cell-Substratum Adhesion
,, and
Centre for Molecular Medicine and
Therapeutics and the Department of Medicine, University of British
Columbia, Vancouver, British Columbia V5Z 4H4, Canada and ¶ Novo
Nordisk, Novo Alle, DK-2880 Bagsvaerd, Denmark
, in A431 epidermoid carcinoma cells. These cells express high levels of the epidermal growth factor
(EGF) receptor and proliferate in response to the autocrine production
of transforming growth factor-. Conversely, EGF stimulation of A431
cells in vitro leads to growth inhibition and triggers the
rapid detachment of these cells from the substratum. Although PTP
expression did not alter the growth characteristics of either unstimulated or EGF-stimulated cells, this phosphatase was associated with increased cell-substratum adhesion. Furthermore, PTP-expressing A431 cells were strikingly resistant to EGF-induced cell rounding. Overexpression of PTP in A431 cells was associated with the
dephosphorylation/activation of specific Src family kinases, suggesting
a potential mechanism for the observed alteration in A431
cell-substratum adhesion. Src kinase activation was dependent on the D1
catalytic subunit of PTP, and there was evidence of association
between PTP and Src kinase(s). PTP expression also led to
increased association of Src kinase with the integrin-associated focal
adhesion kinase, pp125FAK. In addition, paxillin, a Src
and/or pp125FAK substrate, displayed increased levels of
tyrosine phosphorylation in PTP-expressing cells and was associated
with elevated amounts of Csk. In view of these alterations in focal
adhesion-associated molecules in PTP-expressing A431 cells, as well
as the changes in adhesion demonstrated by these cells, we propose that
PTP may have a role in regulating cell-substratum adhesion.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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