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.