Weaver, Valerie M.

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Author: Marinkovich, Matthew P ×

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  • Publication
    Autocrine laminin-5 ligates {alpha}6{beta}4 integrin and activates RAC and NF{kappa}B to mediate anchorange-independent survival of mammary tumors
    (2003-12-22) Zahir, Nastaran; Lakins, Johnathon N; Russell, Alan; Chatterjee, Chandrima; Ming, WenYu; Rozenberg, Gabriela I; Weaver, Valerie M.; Marinkovich, Matthew P
    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 α6β4 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 α6β4 integrin. α6β4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of β4 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 β1 and β4 integrin through activation of NFκB, and overexpression of NFκB 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–α6β4 integrin–RAC–NFκB signaling.
  • Publication
    α6ß4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of α3ß1 integrin
    (2003-09-01) Russell, Alan J; Fincher, Edgar F; Millman, Linda; Smith, Robyn; Vela, Veronica; Waterman, Elizabeth A.; Dey, Clara N; Guide, Shireen; Weaver, Valerie M.; Marinkovich, Matthew P
    Growth factor-induced cell migration and proliferation are essential for epithelial wound repair. Cell migration during wound repair also depends upon expression of laminin-5, a ligand for α6ß4 integrin. We investigated the role of α6ß4 integrin in laminin-5-dependent keratinocyte migration by re-expressing normal or attachment-defective ß4 integrin in ß4 integrin null keratinocytes. We found that expression of ß4 integrin in either a ligand bound or ligand unbound state was necessary and sufficient for EGF-induced cell migration. In a ligand bound state, ß4 integrin supported EGF-induced cell migration though sustained activation of Rac1. In the absence of α6ß4 integrin ligation, Rac1 activation became tempered and EGF chemotaxis proceeded through an alternate mechanism that depended upon α3ß1 integrin and was characterized by cell scattering. α3ß1 integrin also relocalated from cell-cell contacts to sites of basal clustering where it displayed increased conformational activation. The aberrant distribution and activation of α3ß1 integrin in attachment-defective ß4 cells could be reversed by the activation of Rac1. Conversely, in WT ß4 cells the normal cell-cell localization of α3ß1 integrin became aberrant after the inhibition of Rac1. These studies indicate that the extracellular domain of ß4 integrin, through its ability to bind ligand, functions to integrate the divergent effects of growth factors on the cytoskeleton and adhesion receptors so that coordinated keratinocyte migration can be achieved.