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Vol. 11, Issue 7, 2235-2249, July 2000

Differential Role of _1C and _1A Integrin Cytoplasmic Variants in Modulating Focal Adhesion Kinase, Protein Kinase B/AKT, and Ras/Mitogen-activated Protein Kinase Pathways

Mara Fornaro,^* Craig A. Steger,^* Anton M. Bennett, J. Julie Wu,^* and Lucia R. Languino^*

Departments of  ^*Pathology and  Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520

The integrin cytoplasmic domain modulates cell proliferation, adhesion, migration, and intracellular signaling. The ₁ integrin subunits, _1C and _1A, that contain variant cytoplasmic domains differentially affect cell proliferation; _1C inhibits proliferation, whereas _1A promotes it. We investigated the ability of _1C and _1A to modulate integrin-mediated signaling events that affect cell proliferation and survival in Chinese hamster ovary stable cell lines expressing either human _1C or human _1A. The different cytodomains of either _1C or _1A did not affect either association with the endogenous ₂, _V, and ₅ subunits or cell adhesion to fibronectin or TS2/16, a mAb to human ₁. Upon engagement of endogenous and exogenous integrins by fibronectin, cells expressing _1C showed significantly inhibited extracellular signal-regulated kinase (ERK) 2 activation compared with _1A stable cell lines. In contrast, focal adhesion kinase phosphorylation and Protein Kinase B/AKT activity were not affected. Selective engagement of the exogenously expressed _1C by TS2/16 led to stimulation of Protein Kinase B/AKT phosphorylation but not of ERK2 activation; in contrast, _1A engagement induced activation of both proteins. We show that Ras activation was strongly reduced in _1C stable cell lines in response to fibronectin adhesion and that expression of constitutively active Ras, Ras 61 (L), rescued _1C-mediated down-regulation of ERK2 activation. Inhibition of cell proliferation in _1C stable cell lines was attributable to an inhibitory effect of _1C on the Ras/MAP kinase pathway because expression of activated MAPK kinase rescued _1C antiproliferative effect. These findings show that the _1C variant, by means of a unique signaling mechanism, selectively inhibits the MAP kinase pathway by preventing Ras activation without affecting either survival signals stimulated by integrins or cellular interactions with the extracellular matrix. These findings highlight a role for ₁-specific cytodomain sequences in maintaining an intracellular balance of proliferation and survival signals.

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Corresponding author. E-mail address: lucia.languino{at}yale.edu.

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Molecular Biology of the Cell
Vol. 11, 2235-2249, July 2000
Copyright © 2000 by The American Society for Cell Biology

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