Regulation of beta1 Integrin Recycling, Cell Migration and Focal Adhesion Turnover by Cell Adhesion molecule- CD13

Abstract

Abstract CD13 is a multifunctional cell adhesion molecule that is expressed on a variety of cells where we have shown that it modulates receptor mediated endocytosis and ligand internalization to control downstream signaling pathways. In fibroblasts and epithelial cells, CD13 is localized with β1- integrin at focal adhesions (FAs), the sites of communication between the extracellular matrix and the actin cytoskeleton, prompting our exploration of potential contributions of CD13 in focal adhesion turnover, integrin endocytosis and trafficking. Phenotypically, FAs in CD13KO fibroblasts are elongated and irregular with displaced FA accessory proteins, markedly reduced actin stress fibers and fewer microtubule extensions, consistent with a link between CD13 and the control of FA dynamics. In wild type cells, CD13 and β1-integrin co internalize, traffic to Rab5+ early endosomes and recycle to the plasma membrane via Rab11a+ recycling endosomes. Pulse-chase assays with wild type and CD13 phospho tyrosine mutant confirmed that tyrosine phosphorylated CD13 must associate with the active ARF6 for β1-integrin recycling to the membrane to occur. Conversely, the absence of CD13 results in trafficking of internalized β1-integrin from early endosomes to Rab7+ late endosomes/lysosomes and a failure to return to the cell surface. Functionally, in migrating cells CD13 accumulates at the leading edge and co-localizes with IQGAP1 to regulate cell migration and adhesion. In conclusion, CD13 interacts with FAK-Src to control proper localization of focal adhesion proteins regulating focal adhesion turnover and associates with active ARF6-IQGAP1 to promote b1 integrin recycling and cell motility.