Achieving specificity in Akt signaling in cancer.

Since it’s discovery as an effector of PI 3-K (phosphoinositide 3-kinase) (Franke et al., 1995), the serine/threonine kinase Akt (also known as PKB, protein kinase B) has emerged as a critical signal transducer of oncogenic signals in virtually all human solid tumors as well as hematological malignancies. Most cancers display elevated Akt activity and this is achieved by growth factor signaling or through oncogenic mutations in the PI 3-K pathway. In this context, the PI 3-K/Akt pathway has received considerable attention from a therapeutic perspective since proteins that regulate or transduce the PI 3-K signal harbor some of the most frequent genetic lesions in human cancers, including activating mutations in oncogenes as well as LOH (loss of heterozygosity) in tumor suppressors (Engelman, 2009). Similarly, activating oncogenic mutations in the Akt genes have recently been described in various human solid tumors, and small molecule Akt inhibitors are currently being evaluated in clinical trials (Carpten et al., 2007). Akt mediates downstream signaling by phosphorylating substrate proteins that in turn initiate secondary pathways that modulate numerous phenotypes associated with malignancy, including cellular proliferation, evasion from apoptosis, invasive migration, angiogenesis and metabolic reprogramming. Close to 200 Akt substrate proteins have been uncovered either by candidate screening approaches or by whole phospho-proteome mass spectrometry sequencing technologies (Manning and Cantley, 2002, 2007; Moritz et al., 2010). The challenge remains to ascribe a particular cellular function of each identified substrate to a distinct cellular function and its relevance in human pathophysiology. Importantly, there exist three Akt isoforms in humans, Akt1, Akt2 and Akt3, that are derived from distinct genes (Akt1/PKBα, AKT1; Akt2/PKBβ, AKT2; Akt3/PKBγ, AKT3). Recent studies have clearly demonstrated that rather than functioning in cellular signaling in a redundant manner, Akt isoforms have very distinct functions in specific cell lineages with important consequences for cellular physiology. Specific functions of Akt isoforms appear not to be simply due to differential expression patterns or activation profiles, since all three proteins are expressed in virtually all cells and tissues. Similarly, in most examined cells and cancerous tissues, all three Akt isoforms appear to be hyperactive as a result of oncogenic activation of PI 3-K, and therefore any differential, non-redundant signaling via specific Akt isoforms must be derived from more complex mechanisms that result in regulation of a specific isoform. Understanding the precise mechanism(s) that result in activation and signal relay through specific Akt isoforms is of critical importance as it is predicted to have profound consequences for targeted therapy in the PI 3-K/Akt pathway in cancer and other pathophysiologies. Numerous reviews have focused on the details of the mechanisms leading to activation of PI 3-K and in turn regulation of Akt (Engelman et al., 2006; Mora et al., 2004; Vanhaesebroeck and Alessi, 2000). Here, I will focus on the differential functions of Akt isoforms in cancer cell signaling and review current efforts aimed at identifying mechanisms by which Akt isoforms contribute to malignancy in specific, rather than general, settings.