This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Integrins are the major eukaryote receptors for cell adhesion to the extracellular matrix(ECM). Upon ligand binding, integrins cluster to cytoskeleton-linked focal adhesion complexes and play significant roles in cancer cells, affecting signal transduction, gene expression, proliferation, apoptosis regulation, invasion, metastasis, and angiogenesis as well as neovascularization of tumors. To transmit signals, integrins must localize to the plasma membrane and be able to relocate to focal adhesions. While their internalization has been studied extensively, few studies have addressed the regulation of integrin recycling. Our long term goal is to determine the impact of endoctic trafficking on signal transduction mediated through cell adhesion molecules. Since aberrant signal transduction is a prime cause of cancer, dysregulation of endocytic trafficking may have an important bearing on focal adhesion integrity and tumor formation. The central hypothesis is that recycling is key to beta 1-integrin localization to focal adhesions and critical for integrin-mediated cellular signaling events. We will first determine the extent to which beta 1-integrins recycle, by impairing recycling and analyzing levels of beta 1-integrins on the plasma membrane. Next, we will use RNAi to study involvement of proteins in regulating beta 1-integrin recycling. Finally, we will assess the impact of impaired recycling on integrin-mediated signaling and focal adhesion function, analyzing the phospohorylation of substrates localized to focal adhesions and cell motility. Our expectations are: (1) recycling affects the intracellular itinerary of integrins (2) recycling of integrins is regulated by EHD1, Rabenosyn-5, syntaxin 13 and Rab-family proteins (3) impaired recycling will negatively affect localization of integrins and other proteins to focal adhesions, affecting normal siganl tranduction, cell proliferation and motility. These outcomes will have important ramifications for cancer, since a clear understanding of the elements controlling signaling via focal adhesions is essential for development of tools to impair aberrant cell growth.
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