CD98HC-Integrin Signaling in Angiogenesis

Angiogenesis has been figured out as being crucial for growth, progression and metastasis in the majority of solid tumors. Invasion, migration and proliferation of endothelial cells are regulated at least in part by the integrin family. Integrins comprise a large family of cell surface receptor, which attach cells to the matrix and mediate mechanical and chemical signals from it. Many integrin signals converge in cell cycle regulation, directing cells to live or die, to proliferate, or to exit the cell cycle and differentiate. CD98, an early marker of T- cell activation, is an important regulator of integrin-mediated adhesion events. CD98 is a cell surface heterodimer formed by the covalent linkage of CD98 heavy chain (CD98hc) with several different light chains to form amino acid transporters. CD98hc also binds specifically to the integrin beta1A cytoplasmic domain and regulates integrin function. The exact mechanism by which CD98hc associates with and regulates (adhesion dependent) integrin function and what impact the transmembrane (TM) domain of CD98hc plays are still unclear. The specific aim of my postdoctoral fellowship is to investigate the role of the TM domain of CD98hc in adhesion dependent integrin signaling as well as in angiogenesis. Additionally, analyzing mutants of CD98 and CD69, which disrupt CD98hc self-association, should provide further insights in integrin signaling. Studying the molecular mechanisms underlying CD98 adhesion-dependent integrin signaling in angiogenesis will provide new insights in tumor (neo)vascularisation and may have practical applications in the development of novel therapeutic strategies in cancer therapy.