Integrins in Extracellular Matrix Remodeling and Invasion

Integrin signaling is implicated in multiple aspects of matrix remodeling by cancer cells. Experimentally, activation of JNK by FAK in v-Src transformed fibroblasts increases expression of ECM degrading proteases.171 In particular, avb3 integrin, upregulated in melanomas and glioblastomas,172,173 has been shown to combine with diverse RTKs to promote cell migration.174 In addition, avb3 appears to regulate the recruitment and activation of various enzymes involved in ECM degradation at the leading edge of cells, a necessary part of the invasive process.175,176

In normal tissues, expression of a6p4 integrin is associated with cellular compartments that contain populations of rapidly dividing cells. In keratinocytes, binding of a6p4 to laminin-5 permits progression from G1 to S phase in response to EGFand is required for Ras-mediated transformation in culture.162 Upregulation of avb4 is observed in carcinomas, and introduction of b4 is sufficient to enhance the invasive potential of breast carcinoma cells.177 These effects appear to be due to both enhanced activation of integrin-mediated signals and interaction between a6p4 and RTK, involved in invasion. Recruitment of a6p4 by RTKs, such as c-Met, c-Ron, EGFR, and ErbB2, induces tyrosine phosphorylation of the b4 subunit, increasing downstream signaling and enhancing migration and invasion. In the case of Met, this appears to be independent of laminin-5-integrin interaction, whereas ECM binding transactivates EGFR and ErbB2 in an-SFK-dependent manner indicating that a two-way passage of information can occur.178,179

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