Integrins and Downstream Signaling Pathways

Cells secrete insoluble molecules that are assembled and remodeled to form the extracellular matrix (ECM). The ECM provides a scaffold for the appropriate organization of groups of cells into tissues, but also controls multiple aspects of cellular behavior. The majority of the effects of the ECM on cells are mediated via integrins that directly interact with ECM components, such as collagen, vitronectin, laminins, and fibrinogen. Each integrin is composed of a heterodimer formed between an alpha and a beta transmembrane subunit. Over 18 alpha and eight beta subunits have been characterized, and different heterodimers have been shown to bind to distinct but overlapping ECM epitopes.160,161 The intracellular tail of the receptor is found within focal adhesion plaques that are sites of interaction with the actin cytoskeleton and contain numerous signaling molecules, including focal adhesion kinase (FAK), integrin-linked kinase (ILK), Src family kinases (SFKs) and protein kinase C.162 Upregulation of FAK has been observed in multiple invasive human cancers, and FAK-null fibroblasts display defects in migration, particularly in integration of epidermal (EGF) and platelet-derived growth factor (PDGF) mediated promigratory signals.163,164 Integrin mediated activation of FAK, leading to recruitment and activation of SFKs such as c-Src, c-Yes, and c-Fyn, has been extensively studied in tumors. Increased Src activity has been observed in several tumor types, including mammary, colon and pancreatic carcinoma.165 A correlation between Src activity and disease progression led to investigation of the role of Src in tumor invasion and metastasis. Activated c-Src is observed at focal adhesions and genetic ablation of Src interferes with cellular adhesion and spreading. Transformation by Src leads to changes in cell-cell and cell-ECM adhesion and protects cells from anoikis, facilitating anchorage-independent growth in vitro and enhanced invasive behavior of implanted tumors. Activation of Src is dependent on dephosphorylation of a negative regulatory tyrosine residue within the C-terminal domain of the kinase. A number of phosphatases have implicated in activating Src, including PTPa PTPB1, and Shp2. Deletion of PTPB1 or Shp2 is associated with reduced Src activity and perturbation of cell adhesion and spreading.165

Multiple signaling components are activated by FAK and SFKs including ETK, an intracellular tyrosine kinase found at high levels in metastatic carcinoma cells and the ERK/MAPK and JUN kinase cascades, which, in addition to modifying gene expression, can affect motility by direct phosphorylation of cytoskeletal components.166 Activated SFKs phosphorylate and initiate signaling from paxillin and p130CAS.165 Modulation of motility and the actin cytoskeleton occurs principally via the consequent activation of the Rho GTPase family members Rho, Rac, and cdc42. Both Rac and Cdc42 are required for carcinoma motility and invasion, promoting actin polymerization at the leading edge of migrating cells.167 RhoA and RhoC are upregulated in metastatic carcinomas, and RhoC overexpression favors colonization of the lung in an experimental melanoma metastasis model. Rho, acting via two effectors, ROCK and mDIA, regulates actomyosin fiber assembly and contraction, contributing toward pulling forward the trailing edge of cells during migration. Rho-ROCK signaling appears to regulate aspects of carcinoma dissemination and invasion.162 Finally, and importantly, FAK activation can protect tumor cells from anoikis by activating PI3K and PKB and upregulating antiapoptotic protein such as BCL2.162'165

Binding of integrins to the tissue ECM, therefore, governs cellular polarity and migration and provides positional cues that are integrated into the cells response to other stimuli, such as growth factors or cytokines. Although the malignant process is characterized by a partial loss of dependency on ECM-mediated signals, it is equally apparent that it is accompanied by specific changes in integrin expression: upregulation of integrins that facilitate invasion and metastasis and downregulation of those integrins that oppose these processes. Expression of particular oncogenes has been demonstrated to directly modulate integrin expression; however, it appears more likely that these changes occur as a consequence of the selective pressure on cells to adapt to the different environments encountered during invasion and metastasis.170

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