Evidence for a role of p130Cas in JAM‐A‐dependent signaling events (60.3)

Junctional adhesion molecule‐A (JAM‐A) is a tight junction protein that plays a key role in regulation of intestinal mucosal homeostasis. Previous studies have shown that loss of JAM‐A decreases beta‐1 integrin‐mediated cell migration and increases Akt‐dependent proliferation however signaling pathways downstream of JAM‐A remain incompletely defined. Levels of known actin‐dependent regulators of cell migration and proliferation in epithelial cells derived from JAM‐A deficient mice and ex vivo cultures of small intestinal enteroids were thus examined. We observed dramatic changes in p130Cas, a critical signaling component of focal adhesions that is regulated by ABL kinase. Western blots of JAM‐A deficient intestinal epithelial cells (IEC) and enteroids revealed significantly decreased levels of phosphorylated p130Cas. In addition, JAM‐A deficient colonic IEC showed decreased levels of the migration‐regulating integrin beta‐1 in parallel with decreased E‐cadherin, a negative regulator of proliferation. Treatment of cultured IEC with the ABL kinase inhibitor Imatinib resulted in delayed epithelial wound closure, inhibited cell spreading and decreased p130Cas phosphorylation at Y410 similar to that observed with JAM‐A deficiency. These findings suggest that p130Cas may act to transduce JAM‐A‐dependent signals to beta‐1 integrin to regulate migration, and E‐cadherin to inhibit proliferation. Grant Funding Source : Supported by NIH T32 DK007771‐12, Pathobiology of Mucosal/Epithelial Disease