The 3-phosphoinositide-dependent protein kinase-1 (PDK1)  has emerged as a master regulator of the AGC family of protein kinases. It acts as an upstream protein kinase phosphorylating and activating several AGC-family members implicated in the control of cell growth, proliferation, survival and metabolism regulation. These include protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), p90 ribosomal S6 kinase (RSK), the serum and glucocorticoid-induced protein kinase (SGK), as well as several protein kinase C (PKC) isoforms. PDK1 is ubiquitously expressed in cells and surprisingly for an enzyme that regulates at least 23 agoniststimulated AGC kinases, it is constitutively active.  PKB like PDK1 possesses a PtdIns(3,4,5)P3 binding PH domain. Following growth factor or insulin stimulation, the phosphoinositide 3-kinase (PI 3-kinase) is activated and PDK1 and PKB are presumed to co-localise at the membrane due to their mutual ability to bind the newly generated PtdIns(3,4,5)P3 second messenger. These AGC kinases have evolved a distinct mechanism to interact with PDK1 that involves the phosphorylation of a C-terminal, non-catalytic hydrophobic motif, by distinct non-PDK1 upstream kinases, such as the mTOR complexes.  Phosphorylation of the hydrophobic motif is required for PDK1 to interact and phosphorylate the non-PKB AGC kinases and functions as the gatekeeper controlling the activation of these enzymes by PDK1. PDK1 is an attractive target for cancer therapy due to its peculiar role in the regulation of cell motility, a fundamental process both in physiological and in pathological situations.

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