Physiological roles of PKB isoforms in development, growth and glucose metabolism

Protein kinase B (PKB), also known as Akt, is a serine/threonine protein kinase that regulates key events in metabolism, proliferation, cell survival, and differentiation. Importantly, PKB is a major downstream effector of IGF1 and insulin signaling, implicating this kinase in growth control and insulin action. In mammals, there are three isoforms of PKB, PKBα/Akt1, PKBβ/Akt2, and PKBγ/Akt3. These are encoded by distinct genes but share similar structural organization. It has been proposed that such isoforms are uniquely adapted to transmit distinct biological signals. To identify specific physiological functions of the individual isoforms, we and others have generated animal models deficient in PKBα, PKBβ, and PKBγ: Mice lacking PKBα demonstrate increased perinatal mortality and a reduction in body weight, whereas PKBβ-deficient exhibit a diabetes-like syndrome with elevated fasting plasma glucose and peripheral insulin resistance; the present study shows a role of PKBγ in postnatal brain development. These observations indicate that the PKB isoforms have some differential, nonredundant physiological functions. The relatively subtle phenotypes of these mice as well as the viability of the animals suggest, however, that for many functions PKB isoforms are able to compensate for each other. Certain physiological functions of PKB are thus revealed only when total PKB levels are below a critical threshold in particular cell types and tissues. In the present study we analyzed mice doubly deficient for PKBα/PKBγ and PKBβ/PKBγ, respectively, to identify the combined roles of these isoforms in PKB-mediated physiological processes. We show that mice mutant in both PKBα and PKBγ die around embryonic day 12 with severe impairments in growth, cardiovascular development, and organization of the nervous system. In contrast, we found that PKBβ−/−γ−/− mice develop normally and survive with minimal dysfunctions despite a dramatic reduction of total PKB levels in all tissues. In PKBβ−/−γ−/− mice only the PKBα isoform remains to perform essential PKB functions and we show that minimal amounts of PKBα appear to be sufficient for full activation of many downstream targets. Interestingly, even the presence of only a single functional allele of PKBα is sufficient for successful embryonic development and postnatal survival in mice. However, PKBβ−/−γ−/− mice are glucose and insulin intolerant and exhibit a ~25% reduction in body weights compared to wild-type mice. In addition, we found a substantial reduction in relative size and weight of brain and testis, demonstrating an in vivo role for both PKBβ and PKBγ in the determination of whole animal size and individual organ sizes. Taken together, our results provide insights into the PKB isoform hierarchy and their relative importance during early development, growth, and glucose metabolism.