Breaking the Integrin Hinge

Abstract

Integrins are heterodimeric (α, β) cell adhesion receptors. We demonstrate that point mutations in the cytoplasmic domains of both the α and β subunits promote constitutive signaling by the integrin αⅡbβ3. By generating charge reversal mutations, we show these “activating” mutations may act by disrupting a potential salt bridge between the membrane-proximal portions of the α and β subunit cytoplasmic domains. Thus, the modulation of specific interactions between the α and β subunit cytoplasmic domains may regulate transmembrane signaling through integrins. In addition, these activating mutations induce dominant alterations in cellular behavior, such as the assembly of the extracellular matrix. Consequently, somatic mutations in integrin cytoplasmic domains could have profound effects in vivo on integrin-dependent functions such as matrix assembly, cell migration, and anchorage-dependent cell growth and survival. Integrins are heterodimeric (α, β) cell adhesion receptors. We demonstrate that point mutations in the cytoplasmic domains of both the α and β subunits promote constitutive signaling by the integrin αⅡbβ3. By generating charge reversal mutations, we show these “activating” mutations may act by disrupting a potential salt bridge between the membrane-proximal portions of the α and β subunit cytoplasmic domains. Thus, the modulation of specific interactions between the α and β subunit cytoplasmic domains may regulate transmembrane signaling through integrins. In addition, these activating mutations induce dominant alterations in cellular behavior, such as the assembly of the extracellular matrix. Consequently, somatic mutations in integrin cytoplasmic domains could have profound effects in vivo on integrin-dependent functions such as matrix assembly, cell migration, and anchorage-dependent cell growth and survival.