Protein-tyrosine phosphatase α regulates Src family kinases and alters cell-substratum adhesion

被引:120
作者
Harder, KW
Moller, NPH
Peacock, JW
Jirik, FR
机构
[1] Univ British Columbia, Dept Med, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 4H4, Canada
[2] Novo Nordisk AS, DK-2880 Bagsvaerd, Denmark
关键词
D O I
10.1074/jbc.273.48.31890
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 alpha, 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-alpha. Conversely, EGF stimulation of A431 cells in vitro leads to growth inhibit-ion and triggers the rapid detachment of these cells from the substratum. Although PTP alpha 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 alpha-expressing A431 cells were strikingly resistant to EGF-induced cell rounding. Overexpression of PTP alpha 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 alpha, and there was evidence of association between PTP alpha and Src kinase(s). PTP alpha expression also led to increased association of Src kinase with the integrin-associated focal adhesion kinase, pp125(FAK). I,addition, paxillin, a Src and/or pp125(FAK) substrate, displayed increased levels of tyrosine phosphorylation in PTP alpha-expressing cells and was associated with elevated amounts of Csk. In view of these alterations in focal adhesion-associated molecules in PTP alpha-expressing A431 cells, as well as the changes in adhesion demonstrated by these cells, we propose that PTP alpha may have a role in regulating cell-substratum adhesion.
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收藏
页码:31890 / 31900
页数:11
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