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A Key Tyrosine (Y1494) in the β4 Integrin Regulates Multiple Signaling Pathways Important for Tumor Development and Progression

Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts

Requests for reprints: Leslie M. Shaw, Department of Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605. Phone: 508-856-8675; Fax: 508-856-1310; E-mail: leslie.shaw{at}umassmed.edu.

Key Words: β4 integrin • tumor growth • signal transduction • invasion • angiogenesis

Expression of the 6β4 integrin is associated with poor patient prognosis and reduced survival in a variety of human cancers. In recent years, a limited number of in vivo studies have examined the contribution of this integrin receptor to cancer progression and they have revealed that the 6β4 integrin plays a multifaceted role in regulating tumor development and progression. In the current study, we investigated the mechanism by which one tyrosine residue in the β4 subunit cytoplasmic domain, Y1494, contributes to the tumor-promoting functions of the 6β4 integrin in vivo. We show that Y1494 participates in the stimulation of diverse signaling pathways that promote 6β4-dependent tumor growth and invasion. Mutation of Y1494 inhibits the ability of the 6β4 integrin to support anchorage-independent growth in vitro and tumor development and angiogenesis in vivo, a result that mimics the loss of total expression of the β4 subunit. Our results support the hypothesis that Y1494 regulates 6β4-dependent anchorage-independent growth through activation of the extracellular signal-regulated kinase 1/2 signaling pathway, and invasion through the combined activation of phosphatidylinositol 3-kinase and Src. Collectively, our results identify Y1494 as a major regulatory site for signaling from the 6β4 integrin to promote tumor development and progression. [Cancer Res 2008;68(21):8779–87]