No abstract

PKB (protein kinase B, also known as Akt) is a serine/threonine protein kinase that is important in various signalling cascades and acts as a major signal transducer downstream of activated phosphoinositide 3-kinase. There are three closely related isoforms of PKB in mammalian cells, PKBalpha (Akt1), PKBbeta (Akt2) and PKBgamma (Akt3), and this review discusses recent advances in our understanding of the functions of these isoforms in the regulation of adipocyte differentiation, glucose homoeostasis and tumour development.

Some of the characteristics of cancer cells are high rates of cell proliferation, cell survival, and the ability to invade surrounding tissue. The cytoskeleton has an essential role in these processes. Dynamic changes in the cytoskeleton are necessary for cell motility and cancer cells are dependent on motility for invasion and metastasis. The signaling pathways behind the reshaping and migrating properties of the cytoskeleton in cancer cells involve a group of Ras-related small GTPases and their effectors, including the p21-activated kinases (Paks). Paks are a family of serine/threonine protein kinases comprised of six isoforms (Pak 1–6), all of which are direct targets of the small GTPases Rac and Cdc42. Besides their role in cytoskeletal dynamics, Paks have recently been shown to regulate various other cellular activities, including cell survival, mitosis, and transcription. Paks are overexpressed and/or hyperactivated in several human tumors and their role in cell transformation makes them attractive therapeutic targets. Pak-targeted therapeutics may efficiently inhibit certain types of tumors and efforts to identify selective Pak-inhibitors are underway.

To address the issues of isoform redundancy and isoform specificity of the Akt family of protein kinases in vivo, we generated mice deficient in both Akt2 and Akt3. In these mice, only the Akt1 isoform remains to perform essential Akt functions, such as glucose homeostasis, proliferation, differentiation, and early development. Surprisingly, we found that Akt2 ؊/؊ Akt3 ؊/؊ and even Akt1 ؉/؊ Akt2 ؊/؊ Akt3 ؊/؊ mice developed normally and survived with minimal dysfunctions, despite a dramatic reduction of total Akt levels in all tissues. A single functional allele of Akt1 appears to be sufficient for successful embryonic development and postnatal survival. This is in sharp contrast to the previously described lethal phenotypes of Akt1 ؊/؊ Akt2 ؊/؊ mice and Akt1 ؊/؊ Akt3 ؊/؊ mice. However, Akt2 ؊/؊ Akt3 ؊/؊ mice were glucose and insulin intolerant and exhibited an ϳ25% reduction in body weight compared to wild-type mice. In addition, we found substantial reductions in relative size and weight of the brain and testis in Akt2 ؊/؊ Akt3 ؊/؊ mice, demonstrating an in vivo role for both Akt2 and Akt3 in the determination of whole animal size and individual organ sizes.

Akt/protein kinase B (PKB) plays a critical role in the regulation of metabolism, transcription, cell migration, cell cycle progression, and cell survival. The existence of viable knockout mice for each of the three isoforms suggests functional redundancy. We generated mice with combined mutant alleles of Akt1 and Akt3 to study their effects on mouse development. Here we show that Akt1 ؊/؊ Akt3 ؉/؊ mice display multiple defects in the thymus, heart, and skin and die within several days after birth, while Akt1 ؉/؊ Akt3 ؊/؊ mice survive normally. Double knockout (Akt1 ؊/؊ Akt3 ؊/؊ ) causes embryonic lethality at around embryonic days 11 and 12, with more severe developmental defects in the cardiovascular and nervous systems. Increased apoptosis was found in the developing brain of double mutant embryos. These data indicate that the Akt1 gene is more essential than Akt3 for embryonic development and survival but that both are required for embryo development. Our results indicate isoform-specific and dosage-dependent effects of Akt on animal survival and development.In mammals, Akt1, Akt2, and Akt3 (also called protein kinase B␣ [PKB␣], PKB␤, and PKB␥) proteins have similar domain structures and can be activated by numerous growth factors in a phosphatidylinositol 3-kinase-dependent manner (1,3,4,15,23). Once activated, Akt phosphorylates and controls the activities of a diverse group of substrates involved in many cellular and physiological processes, such as cell survival, cell cycle progression, cell growth, metabolism, and angiogenesis (3,10,17,23).Although many proteins have been identified as Akt substrates, the challenge that remains is to show that they actually have an important impact on physiological processes in organisms. Recently, targeted deletion of specific isoforms of Akt in mice has proved to be a powerful tool for elucidating the physiological roles of Akt proteins (5,7,8,13,16,25,27,28). Characterization of such knockout mice has yielded intriguing and surprising results. We and others found that ϳ40% of Akt1 knockout mice die at a neonatal stage with growth retardation, but the other ϳ60% of Akt1 knockout mice survive apparently normally. This suggests that the other two remaining Akt isoforms can, in part, compensate for the loss of one Akt. Knockout of each single isoform gives rise to a distinct phenotype. In general, Akt1 null mice are growth retarded, which may result from placental insufficiency, while Akt2-deficient mice suffer from a type 2 diabetes-like syndrome and Akt3 null mice show impaired brain development (5,7,8,13,16,25,27,28). These observations indicate that the three Akt isoforms have different nonredundant physiological functions. The relatively normal development and distinct physiological functions exhibited by single knockouts may be explained by differences in the tissue distribution and expression levels of these isoforms. We found that Akt1 is the major isoform in placenta and that placenta lacking this protein cannot form a proper vascular labyrinth; this may restric...