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Mobilization and activation of a signaling competent α6β4integrin underlies its contribution to carcinoma progression

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Abstract

This review examines the hypothesis that the function of the α 6β 4 integrin is altered substantially as normal epithelia undergo malignant transformation and progress to invasive carcinoma and that the functions of this integrin contribute to the behavior of aggressive carcinoma cells. Specifically, α 6β 4 functions primarily as an adhesion receptor in normal epithelia, often as a component of hemidesmosomes and associated with intermediate filaments. Factors in the host-tumor microenvironment have the potential to mobilize α 6β 4 from hemidesmosomes and promote its association with F-actin in lamellae and filopodia, a process that is mediated by PKC-dependent phosphorylation of the β 4 cytoplasmic domain. Importantly, this altered localization of α 6β 4 appears to be coupled to an activation of its signaling potential, which may occur through its association with growth factor receptors or lipid rafts, possibilities that are not mutually exclusive. The primal signaling event triggered by α 6β 4 appears to be activation of PI3-K and this activation has profound consequences on the migration, invasion and survival of carcinoma cells. Arguably, the ability of α 6β 4 to stimulate the PI3-K-dependent translation of VEGF and possibly other growth factors may be the most significant contribution of this integrin to carcinoma because of the potential autocrine and paracrine effects of these factors.

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  1. Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, 02215

    Elizabeth A. Lipscomb

  2. Department of Cancer Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA, 01605

    Arthur M. Mercurio

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  1. Elizabeth A. Lipscomb
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Correspondence to Arthur M. Mercurio.

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Lipscomb, E.A., Mercurio, A.M. Mobilization and activation of a signaling competent α6β4integrin underlies its contribution to carcinoma progression. Cancer Metastasis Rev 24, 413–423 (2005). https://doi.org/10.1007/s10555-005-5133-4

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