Abstract
Integrins αVβ6 and αVβ8 are specialized for recognizing pro-TGF-β and activating its growth factor by releasing it from the latency imposed by its surrounding prodomain. The integrin αVβ8 is atypical among integrins in lacking sites in its cytoplasmic domain for binding to actin cytoskeleton adaptors. Here, we examine αVβ8 for atypical binding to pro-TGF-β1. In contrast to αVβ6, αVβ8 has a constitutive extended-closed conformation, and binding to pro-TGF-β1 does not stabilize the open conformation of its headpiece. Although Mn2+ potently activates other integrins and increases affinity of αVβ6 for pro-TGF-β1 25- to 55-fold, it increases αVβ8 affinity only 2- to 3-fold. This minimal effect correlates with the inability of Mn2+ and pro-TGF-β1 to stabilize the open conformation of the αVβ8 headpiece. Moreover, αVβ8 was inhibited by high concentrations of Mn2+ and was stimulated and inhibited at markedly different Ca2+ concentrations than αVβ6 These unusual characteristics are likely to be important in the still incompletely understood physiologic mechanisms that regulate αVβ8 binding to and activation of pro-TGF-β.