J. Clin. Invest. 109: 999–1006 (2002). DOI: 10.1172/JCI200215468. them are involved in the modulation of integrin affinity. Potential candidates for such regulation are ICAP-1 and TAP-20, which decrease, and β3-endonexin, which increases integrin-mediated adhesion in cells overexpressing these molecules. Intracellular signaling mechanisms, for example phosphorylation of ICAP-1 by CaMKII, are suggested to modulate the binding of these molecules to integrin and thereby the affinity state. Cell attachment can be induced not only by affinity regulation, but also by clustering of integrins, which leads to increased adhesive avidity. Such clusters are present in focal adhesions, readily detectable cellmatrix contacts that have been extensively studied in cultured fibroblasts. Increased lateral mobility of integrins in the membrane might also be important for efficient ligand binding. In leukocytes, even prior to ligand binding, integrins seem to be associated with the actin network, which constrains integrin mobility and ligand binding. Releasing this contact by proteolytic digestion of the integrin connections with the cytoskeleton results in a rapid increase in lateral mobility of integrins, which increases the chance of ligand encounters and facilitates integrin aggregation into high-avidity clusters (4).