PDK2: the missing piece in the receptor tyrosine kinase signaling pathway puzzle

Abstract

Activation of members of the protein kinase AGC (cAMP dependent, cGMP dependent, and protein kinase C) family is regulated primarily by phosphorylation at two sites: a conserved threonine residue in the activation loop and a serine/threonine residue in a hydrophobic motif (HM) near the COOH terminus. Although phosphorylation of these kinases in the activation loop has been found to be mediated by phosphoinositide-dependent protein kinase-1 (PDK1), the kinase(s) that catalyzes AGC kinase phosphorylation in the HM remains uncharacterized. So far, at least 10 kinases have been suggested to function as an HM kinase or the so-called “PDK2,” including mitogen-activated protein (MAP) kinase-activated protein kinase-2 (MK2), integrin-linked kinase (ILK), p38 MAP kinase, protein kinase Cα (PKCα), PKCβ, the NIMA-related kinase-6 (NEK6), the mammalian target of rapamycin (mTOR), the double-stranded DNA-dependent protein kinase (DNK-PK), and the ataxia telangiectasia mutated (ATM) gene product. However, whether any or all of these kinases act as a physiological HM kinase remains to be established. Nonetheless, available data suggest that multiple systems may be used in cells to regulate the activation of the AGC family kinases. It is possible that, unlike activation loop phosphorylation, phosphorylation of the HM site in the different AGC family kinases is mediated by distinct kinases. In addition, phosphorylation of the AGC family kinase at the HM site could be cell type, signaling pathway, and substrate specific. Identification and characterization of the bonafide HM kinase(s) will be essential to verify these hypotheses.

Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence

“…However, other kinases may also perform this function in different contexts (27)(28)(29). We therefore investigated whether RICTOR-mTOR was required for heparanase-induced AKT Ser-473 phosphorylation.…”

Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?

“…The kinase that phosphorylates Akt on T308 is 3-phosphoinositide-dependent protein kinase-1 (PDK1), an AGC kinase that is recruited by D3 phosphoinositides. The identity of the PDK2 that phosphorylates S473 in vivo has been debated for over 10 years, and it has variously been suggested to be Akt itself, DNA-protein kinase (DNA-PK), integrin linked kinase (ILK), protein kinase C (PKC)a, ATM and other kinases as well (Dong and Liu, 2005). However, a recent report by surprisingly demonstrates that the PDK2 for Akt is, in fact, mTORC2.…”

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

“…Serine phosphorylation by PDK-All of the kinases require prior phosphorylation by the phosphoinositide dependent kinase 1, PDK1 [37], and PKCβII has been shown to act as a PDK2 activity in some cases [38]. This phosphorylation occurs on the catalytic domain or activation loop.…”

“…The activation of PKCβ isoforms is regulated by phospholipids, diacylglycerol, calcium, phospholipids and phosphoinositides as well as phorbol esters and they translocate to unique subcellular sites following activation. As mentioned earlier, all of the kinases require prior phosphorylation by the phosphoinositide dependent kinase 1, PDK1 [77], and PKCβII has been shown to act as a PDK2 activity in some cases [38] for activation of the catalytic domain. This phosphorylation is followed by two autophosphorylations within the C-terminal domain on most isoforms.…”