Proto-oncogene tyrosine-protein kinase receptor Ret
positive regulation of cell adhesion mediated by integrin
RET-mediated cell adhesion and migration require multiple integrin subunits.
<h4>Context</h4>The RET receptor tyrosine kinase is an important mediator of several human diseases, most notably of neuroendocrine cancers. These diseases are characterized by aberrant cell migration, a process tightly regulated by integrins.<h4>Objective</h4>Our goals were to investigate the role of integrins in RET-mediated migration in two neoplastic cell models: the neural-derived cell line SH-SY5Y, and the papillary thyroid carcinoma cell line TPC-1. We also evaluated whether multiple integrin subunits have a role in RET-mediated cell migration.<h4>Design</h4>We evaluated the expression and activation of integrins in response to RET activation using standard cell adhesion and migration (wound-healing) assays. We examined focal adhesion formation, using integrin-paxillin coimmunoprecipitations and immunofluorescence, as an indicator of integrin activity.<h4>Results</h4>Our data indicate that β1 integrin (ITGB1) is expressed in both SH-SY5Y and TPC-1 cell lines and that these cells adhere strongly to matrices preferentially associated with ITGB1. We showed that RET can activate ITGB1, and that RET-induced cell adhesion and migration require ITGB1. Furthermore, we showed that β3 integrin (ITGB3) also plays a role in RET-mediated cell adhesion and migration in vitro and ITGB3 expression correlates with RET-mediated invasion in a mouse tumor xenograft model, suggesting that RET mediates the activity of multiple integrin subunits.<h4>Conclusions</h4>Our data are the first to show that multiple integrin subunits contribute to cell adhesion and migration downstream of RET, suggesting that coordinated signaling through these pathways is important for cell interactions with the microenvironment during tumor invasion and progression.