Akt, also known as protein kinase B (PKB), is a serine ⁄ threonine protein kinase that plays a pivotal role in many physiological processes, including metabolism, development, cell cycle progression, migration and survival [1][2][3][4]. The Akt subfamily of protein kinases consists of three isoforms -Akt1, Akt2 and Akt3 (also termed PKBa, PKBb and PKBc) -which are the products of distinct genes. All three proteins share a conserved tertiary structure of an N-terminal pleckstrin homology domain, a kinase domain and a C-terminal regulatory domain containing the hydrophobic motif phosphorylation site [5]. While the homology between the three isoforms allows for a degree of functional redundancy [1], there also seems to be considerable scope for isoform-specific activation and substrate specificity [3,6].Akt plays an integral role in the phosphoinositide 3-kinase (PI3K) signaling pathways. PI3K pathways are activated in response to extracellular signals mediated by cell-surface receptors of the G protein-coupled receptor (GPCR), integrin and growth factor ⁄ receptor tyrosine kinase (RTK) superfamilies. Receptor-mediated activation of PI3K results in the generation of phosphatidylinositol (3,4,5)-trisphosphate from phosphatidylinositol (4,5)-bisphosphate, a reaction that is reversed by the enzymes phosphatase and tensin homologue (PTEN) and SH2-domain-containing inositol polyphosphate 5-phosphatase (SHIP). Both Akt and

Tuberin, a tumor suppressor protein, is involved in various cellular functions including survival, proliferation, and growth. It has emerged as an important effector regulated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). Regulation of tuberin by RTKs and GPCRs is highly complex and dependent on the type of receptors and their associated signaling molecules. Apart from Akt, the first kinase recognized to phosphorylate and inactivate tuberin upon growth factor stimulation, an increasing number of kinases upstream of tuberin have been identified. Furthermore, recruitment of different scaffolding adaptor components to the activated receptors appears to play an important role in the regulation of tuberin activity. More recently, the differential regulation of tuberin by various G protein family members have also been intensively studied, it appears that G proteins can both facilitate (e.g., G_i/o) as well as inhibit (e.g., G_q) tuberin phosphorylation. In the present review, we attempt to summarize our emerging understandings of the roles of RTKs, GPCRs, and their cross-talk on the regulation of tuberin.