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Since the discovery of the serine/threonine kinase Akt/PKB two decades ago, it has been implicated in an increasing number of physiological and pathological processes [24]. Many studies have shown that Akt hyperactivation is a common characteristic in a wide range of human tumours [2]. Akt regulates diverse cellular processes such as apoptosis, cell proliferation, differentiation, migration and angiogenesis. Furthermore, a number of studies have shown that overexpression and/or activation of Akt renders tumour cells resistant to chemotherapeutic drugs and signalling pathway inhibitors such as Gleevec, Iressa and Herceptin [21]. siRNA-mediated knockdown of Akt significantly reduces tumor growth and invasiveness and induces apoptosis [23]. These observations have made it an attractive target for the development of anticancer therapeutics, and it has been postulated that inhibition of Akt alone or in combination with standard cancer chemotherapeutics will reduce the apoptotic threshold [12]. To date, three Akt family members have been identified in mammals. These are transcribed from distinct genetic loci, termed Akt1/PKBα, Akt2/PKBβ and Akt3/PKBγ. Akt family members share a similar domain structure [26] and all three proteins are expressed in all cells and tissues.  Oncogenic mutations in the phosphoinositide (PI) 3-kinase (PI3-K) pathway lead to hyperactivation of all three Akt isoforms [27]. Akt can be activated by steroid hormones or growth factors, downstream of constitutively active Ras and Src pathways [18]. Properly regulated activation of Akt depends on the integrity of the pleckstrin homology (PH) domain, which mediates its membrane translocation and subsequent phosphorylation at two regulatory sites, Thr308 in the kinase activation loop, and Ser473 in the C-terminal domain of the Akt family, only AKT2 mRNA is frequently overexpressed in human cancers [17]. Activation of Akt can also result from a dominant mutation that was identified in human tumours [3] and a point mutation of AKT2 has been reported in familial diabetes [9]. Ectopic expression of constitutively active Akt and even wild-type Akt2 results in oncogenic transformation in vitro and in vivo [4]. For these reasons, many clinical trials are underway using recently developed small molecule inhibitors targeting the PI3K/Akt pathway.  To date, more than 200 Akt substrates have been identified. However, isoform specificity has been studied for only a few, including the Akt1-specific targets p21 [13] and SKP2 [8], and the Akt2-specific targets MDM2 and AS160 [22]. Moreover, none of these targets can account for the differential effects of Akt isoforms on invasive migration [10]. A recent report raises concerns that Akt1 and Akt2 isoforms have opposing functions in the regulation of carcinoma migration. Bae et al. reported the first evidence for the different functions of Akt isoforms, from Akt1, Akt2 and Akt3 knockout mouse studies. Akt1 null mice displayed growth retardation, Akt2 null mice developed insulin-resistant diabetes (because of its dominant role in metabolic signalling in the liver), and Akt3 null mice revealed a reduced brain size. Other in vivo studies using isoform-specific RNAi or inhibitors have highlighted the different functions of the Akt isoforms, especially in modulating motility in breast cancer [1, 6, 7].   In contrast, several in vitro studies of ectopic expression of Akt proteins indicated that various Akt isoforms could stimulate motility [25] and enhance migration [11]. Consistent with the above study, other in vivo studies using Akt1 knockout mice resulted in fewer metastases, with the conclusion that Akt1 signalling is positively associated with invasion leading to metastasis [16]. A study of constitutively active Akt1 in the mouse mammary gland by Hutchinson et al. reported that Akt1 suppresses mammary tumor invasion [14]. Another in vitro assay also demonstrated that Akt1 suppresses breast cancer cell migration by enhancing the proteasomal degradation of the nuclear factor of activated T cells transcription factor, which in turn promotes the expression of invasion genes such as COX2 [28]. More recent studies have shown that Akt1 can block cell migration through tuberous sclerosis complex 2 [19], its silencing induces epithelial-mesenchymal transition in MCF10A cells and in the same cells Akt2 actually enhances this phenotype [15]. The specific substrates of Akt2 responsible for enhancing cell migration have not yet been identified. More recently, Chin et al. reported more mechanistic insights as to how Akt isoforms differentially control cell migration in breast cancer cells, showing that the actin bundling protein palladin is an exclusive Akt1 substrate that is not phosphorylated by Akt2 and is required for efficient breast cancer cell migration [5]. A similar in vivo study from Maroulakou et al. also showed a suppression of metastasis, consistent with Akt1 functioning as a metastasis suppressor [20]. This same study also noted that knockout of Akt2 in mice decreased metastases, consistent with Akt2 functioning as an enhancer of metastasis. Moreover, it has been shown that the membrane recruitment of Akt2 in insulin-stimulated adipocytes was faster than Akt1, and was dependent on the PH domain and the Akt2 linker region [10]. Furthermore, Chin et al. showed that the Akt1 linker region determines the selectivity of Akt1 over Akt2 in the phosphorylation of palladin [5]. Whether the linker region contains specific microdomains or any other determinants that dictate Akt isoform substrate selectivity is not known. Regardless, specific substrates of Akt isoforms that are responsible for transducing distinct phenotypes clearly do exist. These new data have cast Akt itself as the lead role in the already crowded stage of Akt signalling.     In summary, there is now overwhelming evidence that Akt1 and Akt2 have opposing functions in modulating phenotypes associated with migration and invasion. Eventhough the inhibition of Akt signalling should foil local tumor growth, it could promote invasion and metastasis in certain settings. Emerging evidence that the three Akt isoforms have distinct substrates with distinct physiological outcomes will require us to re-evaluate the aim of global inhibition of Akt in cancer therapy.

Opposing roles of the oncogene Akt isoforms in tumour progression: is there a dark side to Akt pathway inhibition?