Mobilization and activation of a signaling competent alpha6beta4integrin underlies its contribution to carcinoma progression.
This review examines the hypothesis that the function of the alpha 6beta 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, alpha 6beta 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 alpha 6beta 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 beta 4 cytoplasmic domain. Importantly, this altered localization of alpha 6beta 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 alpha 6beta 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 alpha 6beta 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.
Lipscomb
Elizabeth A
EA
Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Mercurio
Arthur M
AM
D000199:Actins / Q000378:metabolism; D000818:Animals; D002277:Carcinoma / Q000473:pathology*; D002465:Cell Movement; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D003593:Cytoplasm / Q000378:metabolism; D003896:Desmosomes / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation; D004848:Epithelium / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism* / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D014158:Transcription, Genetic
D000199:Actins; D039161:Integrin alpha6beta4; D016023:Integrins; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C