Weaver, Valerie M.
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Publication Hypoxia-inducible Factor Regulates αvß3 Integrin Cell Surface Expression(2005-04-01) Cowden Dahl, Karen D.; Weaver, Valerie M.; Robertson, Sarah E.; Simon, M. CelesteHypoxia-inducible factor (HIF)-deficient placentas exhibit a number of defects, including changes in cell fate adoption, lack of fetal angiogenesis, hypocellularity, and poor invasion into maternal tissue. HIF is a heterodimeric transcription factor consisting of α and ß aryl hydrocarbon receptor nuclear translocator or ARNT) subunits. We used undifferentiated trophoblast stem (TS) cells to characterize HIF-dependent adhesion, migration, and invasion. Arnt-/- and Hifα-/- TS cells exhibit reduced adhesion and migration toward vitronectin compared with wild-type cells. Furthermore, this defect is associated with decreased cell surface expression of integrin αvß3 and significantly decreased expression of this integrin in focal adhesions. Because of the importance of adhesion and migration in tumor progression (in addition to placental development), we examined the affect of culturing B16F0 melanoma cells in 1.5% oxygen (O2). Culturing B16F0 melanoma cells at 1.5% O2 resulted in increased αvß3 integrin surface expression and increased adhesion to and migration toward vitronectin. Together, these data suggest that HIF and O2 tension influence placental invasion and tumor migration by increasing cell surface expression of αvß3 integrin.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 PInvasive 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 Peering from the outside in: viscoelastic properties of the extracellular matrix dictate spatial organization and apoptosis resistance in mammary epithelial cells(2002-10-23) Zahir, N.; Yeung, T.; Janmey, Paul; Ming, W.; Weaver, Valerie M.The compliance of the extracellular matrix (ECM) differs between tissues and is altered in tumors. We examined the consequence of modifying the viscoelastic properties of the ECM on mammary epithelial cell (MEC) morphogenesis and apoptosis regulation. Results showed that the elastic modulus of the ECM exerts a profound effect on MEC tissue organization and gene expression that correlates with changes in actin organization and apoptosis resistance. Altering the rigidity of the ECM directly influences integrin expression and additionally modifies integrin-induced gene expression in association with actin reorganization. These data suggest that the compliance of the ECM may cooperatively regulate cell behavior by altering integrin function. Studies are now underway to investigate the possibility that these effects are mediated via changes in integrin-actin cytoskeletal dynamics.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 PGrowth 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.