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

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 f...

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Bibliographic Details
Published in:The Journal of cell biology 2003-12, Vol.163 (6), p.1397-1407
Main Authors: Zahir, Nastaran, Lakins, Johnathon N, Russell, Alan, Ming, WenYu, Chatterjee, Chandrima, Rozenberg, Gabriela I, Marinkovich, M Peter, Weaver, Valerie M
Format: Article
Language:English
Subjects:
Autocrine Communication - drug effects
Autocrine Communication - physiology
Basement Membrane - metabolism
Breast cancer
Breast Neoplasms - metabolism
Breast Neoplasms - physiopathology
Carcinoma - metabolism
Carcinoma - physiopathology
Cell Adhesion - drug effects
Cell Adhesion - physiology
Cell Adhesion Molecules - metabolism
Cell Line, Tumor
Cell Survival - drug effects
Cell Survival - physiology
Cells
Epidermal Growth Factor - pharmacology
Humans
Integrin alpha6beta4 - metabolism
Kalinin
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
Membranes
Neoplasm Invasiveness - physiopathology
NF-kappa B - metabolism
Protein Structure, Tertiary - physiology
Proteins
rac GTP-Binding Proteins - metabolism
Skin
Tumors
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Summary: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.
ISSN:0021-9525
1540-8140