Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.

TitleAutocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.
Publication TypeJournal Article
Year of Publication2003
AuthorsZahir N, Lakins JN, Russell A, Ming WY, Chatterjee C, Rozenberg GI, M Marinkovich P, Weaver VM
JournalJ Cell Biol
Volume163
Issue6
Pagination1397-407
Date Published2003 Dec 22
ISSN0021-9525
KeywordsAutocrine Communication, Basement Membrane, Breast Neoplasms, Carcinoma, Cell Adhesion, Cell Adhesion Molecules, Cell Line, Tumor, Cell Survival, Epidermal Growth Factor, Humans, Integrin alpha6beta4, MAP Kinase Signaling System, Neoplasm Invasiveness, NF-kappa B, Protein Structure, Tertiary, rac GTP-Binding Proteins
Abstract

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express alpha6beta4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail-truncated alpha6beta4 integrin. alpha6beta4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of beta4 integrin is necessary for basal and epidermal growth factor-induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional beta1 and beta4 integrin through activation of NFkappaB, and overexpression of NFkappaB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5-alpha6beta4 integrin-RAC-NFkappaB signaling.

DOI10.1083/jcb.200302023
Alternate JournalJ. Cell Biol.
PubMed ID14691145
PubMed Central IDPMC2173718
Grant ListCA 78731 / CA / NCI NIH HHS / United States
P01 AR44-012 / AR / NIAMS NIH HHS / United States
T32 HL07954-03 / HL / NHLBI NIH HHS / United States