COMPLEMENTATION OF DOMINANT SUPPRESSION IMPLICATES CD98 IN INTEGRIN ACTIVATION

The integrin family of adhesion receptors are involved in cell growth, migration and tumour metastasis(1). Integrins are heterodimeric prote ins composed of an alpha and a beta subunit, each with a large extrace llular, a single transmembrane, and a short cytoplasmic domain. The dy namic regulation of integrin affinity for ligands in response to cellu lar signals is central to integrin function(2). This process is energy dependent and is mediated through integrin cytoplasmic domains(3). Ho wever, the cellular machinery regulating integrin affinity remains poo rly understood. Here we describe a genetic strategy to disentangle int egrin signalling pathways. Dominant suppression occurs when overexpres sion of isolated integrin beta(1) cytoplasmic domains blocks integrin activation. Proteins involved in integrin signalling were identified b y their capacity to complement dominant suppression in an expression c loning scheme. CD98, an early T-cell activation antigen that associate s with functional integrins(4), was found to regulate integrin activat ion. Furthermore, antibody-mediated crosslinking of CD98 stimulated be ta(1) integrin-dependent cell adhesion. These data indicate that CD98 is involved in regulating integrin affinity, and validate an unbiased genetic approach to analysing integrin signalling pathways.