Molecular Analysis of the alpha6beta4 Integrin

Sloan-Kettering Inst Can Research, New York NY

Investigators

Linked publications & trials

Abstract

The a6|34 integrin binds to the basal lamina component laminin-5. Integrin <x6|34 signaling proceeds through Src Family Kinase (SFK)-mediated phosphorylation of the cytoplasmic domain of (34, recruitment of the adaptor She, and activation of Ras and PI-3K. Upon dephosphorylation, the cytoplasmic domain of (34 mediates assembly of hemidesmosomes, strengthening adhesion to the basement membrane. To analyze the role of |34 signaling in the absence of loss of adhesion strengthening, we have generated mice carrying a deletion of the C-terminal, signaling segment of the (34 tail. These mice develop normally but display defects in post-natal angiogenesis and wound repair (Nikolopoulos et al., 2004;2005). To examine if (34signaling plays a role during ErbB2-mediated mammary tumorigenesis, we have introduced the targeted deletion of the (34 signaling domain in MMTV-A/etv mice and have found that loss of (34signaling suppresses mammary tumor onset and invasive growth (Quo et al., 2006). Under the extension of this R37 Award, we plan to examine the mechanism by which the (34 integrin promotes tumor angiogenesis. Our preliminary studies suggest that a6|34 promotes angiogenesis in response to netrins. The netrins are laminin-like proteins best known for their roles in neuronal guidance, but recent data - including our won - suggest that they also participate in angiogenesis. We propose to: 1) examine the ability of netrins to induce tumor angiogenesis and lymphangiogenesis;2) determine if loss of (34 signaling in endothelial cells impairs netrin- mediated angiogenesis;3) examine the mechanism of binding of netrins to a6|34;and 4) study netrin-induced signaling endothelial cells. Taken together, these experiments should increase our understanding of the role of a6|34 and netrins in tumor angiogenesis.