Integrins ?V?6 and ?V?8 are specialized for recognizing pro-TGF-? and activating its growth factor by releasing it from the latency imposed by its surrounding prodomain. The integrin ?V?8 is atypical among integrins in lacking sites in its cytoplasmic domain for binding to actin cytoskeleton adaptors. Here, we examine ?V?8 for atypical binding to pro-TGF-?1. In contrast to ?V?6, ?V?8 has a constitutive extended-closed conformation, and binding to pro-TGF-?1 does not stabilize the open conformation of its headpiece. Although Mn2+ potently activates other integrins and increases affinity of ?V?6 for pro-TGF-?1 25- to 55-fold, it increases ?V?8 affinity only 2- to 3-fold. This minimal effect correlates with the inability of Mn2+ and pro-TGF-?1 to stabilize the open conformation of the ?V?8 headpiece. Moreover, ?V?8 was inhibited by high concentrations of Mn2+ and was stimulated and inhibited at markedly different Ca2+ concentrations than ?V?6 These unusual characteristics are likely to be important in the still incompletely understood physiologic mechanisms that regulate ?V?8 binding to and activation of pro-TGF-?.