8-CPT-2OMe-cAMP inhibits HGF-induced migration in the absence of cadherin-mediated cell-cell adhesion

Abstract

Rap1 is an important regulatory proteins involved in cell-cell adhesion and cell-matrix adhesion. The regulation of cell adhesion is important for cell migration. Cell migration is a vital process required for embryogenesis, wound healing and the immune response. It is also involved in certain pathological processes, including cancer cell metastasis. In this thesis, I show that when endogenous Rap1 is activated using the Epac-specific cAMP analogue 8-pCPT-2’OMe-cAMP, epithelial cells no longer respond to migration-inducing growth factors. This inhibition is not caused by an effect of Rap1 on E-cadherin-dependent cell-cell junctions or a direct inhibition of the growth factor signaling pathways, but is mediated by specific effects on the migration machinery. Cells treated with the cAMP analogue display an increase in focal adhesion size and number and a decrease in lamellipodial protrusion. It remains unclear via which Rap1 effector proteins this/these effect(s) is/are mediated. Furthermore, the major signaling pathways involved in focal adhesion dynamics, are unaffected by activation of Rap1. This lead to the hypothesis that Rap1 may affect the linkage between the integrin and the actin cytoskeleton, to control cell migration.