BREAKING THE INTEGRIN HINGE - A DEFINED STRUCTURAL CONSTRAINT REGULATES INTEGRIN SIGNALING

Integrins are heterodimeric (alpha, beta) cell adhesion receptors, We demonstrate that point mutations in the cytoplasmic domains of both th e alpha and beta subunits promote constitutive signaling by the integr in alpha(IIIb)beta(3). BY generating charge reversal mutations, we sho w these ''activating'' mutations may act by disrupting a potential sal t bridge between the membrane-proximal portions of the alpha and beta subunit cytoplasmic domains, Thus, the modulation of specific interact ions between the alpha and beta subunit cytoplasmic domains may regula te transmembrane signaling through integrins, In addition, these activ ating mutations induce dominant alterations in cellular behavior, such as the assembly of the extracellular matrix, Consequently, somatic mu tations in integrin cytoplasmic domains could have profound effects in vivo on integrin-dependent functions such as matrix assembly, cell mi gration, and anchorage-dependent cell growth and survival.