PDPK1

In biochemistry, PDK1 is a master kinase, which is crucial for the activation of AKT/PKB and many other AGC kinases including PKC, S6K, SGK. An important role for PDK1 is in the signalling pathways activated by several growth factors and hormones including insulin signalling. Mice lacking PDK1 die during early embryonic development, indicating that this enzyme is critical for transmiting the growth-promoting signals nescessary for normal mammalian development. Mice that are deficient in PDK1 have a ~40% decrease in body mass, mild glucose intolerance, and are resitant to cancer brought about by hyperactivation of the PI3K pathway (PTEN+/-).

It is also known as "PDPK1" ("PDK" can be confused with pyruvate dehydrogenase kinase.) PBB_Summary
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Etymology

PDK1 stands for 3-phosphoinositide-dependent protein kinase 1. PDK1 functions downstream of PI3K through PDK1's interaction with membrane phospholipids including phosphatidylinositols, phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate . PI3K indirectly regulates PDK1 by phosphorylating phosphatidylinositols which in turn generates phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate . However, PDK1 is believed to be constitively active and does not always require phosphatidylinositols for its activities.

Phosphatidylinositols is only required for the activation at the membrane of some substrates including AKT. PDK1 however does not require membrane lipid binding for the efficient phosphorylation of most of its substrates in the cytosol (not at the cell membrane).

tructure

The structure of PDK1 can be divided into two domains; the kinase or catalytic domain and the PH domain. The PH domain functions mainly in the interaction of PDK1 with phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate which is important in localization and activation of some of membrane associated PDK1's substrates including AKT.

The kinase domain has three ligand binding sites; the substrate binding site, the ATP binding site, and the docking site (also known as PIF pocket). Several PDK1 substrates including AKT and Protein kinase C, require the binding at this docking site. Small molecule allosteric inhibitors of PDK1 were shown to selectively inhibit activation of substrates that require docking site interaction. However, these inhibitors do not bind to the active site and allow PDK1 to activate other substrates that do not require docking site interaction. PDK1 is constitively active and at present, there is no known inhibitor proteins for PDK1.

The activation of PDK1's main effector, AKT, is believed to require a proper orientation of the kinase and PH domains of PDK1 and AKT at the membrane.

References

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Further reading

PBB_Further_reading
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*cite journal | author=Vanhaesebroeck B, Alessi DR |title=The PI3K-PDK1 connection: more than just a road to PKB. |journal=Biochem. J. |volume=346 Pt 3 |issue= |pages= 561–76 |year= 2000 |pmid= 10698680 |doi=
*cite journal | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=
*cite journal | author=Alessi DR, James SR, Downes CP, "et al." |title=Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. |journal=Curr. Biol. |volume=7 |issue= 4 |pages= 261–9 |year= 1997 |pmid= 9094314 |doi=
*cite journal | author=Moser BA, Dennis PB, Pullen N, "et al." |title=Dual requirement for a newly identified phosphorylation site in p70s6k. |journal=Mol. Cell. Biol. |volume=17 |issue= 9 |pages= 5648–55 |year= 1997 |pmid= 9271440 |doi=
*cite journal | author=Alessi DR, Deak M, Casamayor A, "et al." |title=3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. |journal=Curr. Biol. |volume=7 |issue= 10 |pages= 776–89 |year= 1998 |pmid= 9368760 |doi=
*cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, "et al." |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=
*cite journal | author=Meier R, Alessi DR, Cron P, "et al." |title=Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta. |journal=J. Biol. Chem. |volume=272 |issue= 48 |pages= 30491–7 |year= 1997 |pmid= 9374542 |doi=
*cite journal | author=Alessi DR, Kozlowski MT, Weng QP, "et al." |title=3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro. |journal=Curr. Biol. |volume=8 |issue= 2 |pages= 69–81 |year= 1998 |pmid= 9427642 |doi=
*cite journal | author=Dalby KN, Morrice N, Caudwell FB, "et al." |title=Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90rsk that are inducible by MAPK. |journal=J. Biol. Chem. |volume=273 |issue= 3 |pages= 1496–505 |year= 1998 |pmid= 9430688 |doi=
*cite journal | author=Pullen N, Dennis PB, Andjelkovic M, "et al." |title=Phosphorylation and activation of p70s6k by PDK1. |journal=Science |volume=279 |issue= 5351 |pages= 707–10 |year= 1998 |pmid= 9445476 |doi=
*cite journal | author=Stephens L, Anderson K, Stokoe D, "et al." |title=Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. |journal=Science |volume=279 |issue= 5351 |pages= 710–4 |year= 1998 |pmid= 9445477 |doi=
*cite journal | author=Walker KS, Deak M, Paterson A, "et al." |title=Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha. |journal=Biochem. J. |volume=331 ( Pt 1) |issue= |pages= 299–308 |year= 1998 |pmid= 9512493 |doi=
*cite journal | author=Anderson KE, Coadwell J, Stephens LR, Hawkins PT |title=Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B. |journal=Curr. Biol. |volume=8 |issue= 12 |pages= 684–91 |year= 1998 |pmid= 9637919 |doi=
*cite journal | author=Le Good JA, Ziegler WH, Parekh DB, "et al." |title=Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. |journal=Science |volume=281 |issue= 5385 |pages= 2042–5 |year= 1998 |pmid= 9748166 |doi=
*cite journal | author=Currie RA, Walker KS, Gray A, "et al." |title=Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. |journal=Biochem. J. |volume=337 ( Pt 3) |issue= |pages= 575–83 |year= 1999 |pmid= 9895304 |doi=
*cite journal | author=Kobayashi T, Cohen P |title=Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. |journal=Biochem. J. |volume=339 ( Pt 2) |issue= |pages= 319–28 |year= 1999 |pmid= 10191262 |doi=
*cite journal | author=Balendran A, Casamayor A, Deak M, "et al." |title=PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. |journal=Curr. Biol. |volume=9 |issue= 8 |pages= 393–404 |year= 1999 |pmid= 10226025 |doi=
*cite journal | author=Park J, Leong ML, Buse P, "et al." |title=Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. |journal=EMBO J. |volume=18 |issue= 11 |pages= 3024–33 |year= 1999 |pmid= 10357815 |doi= 10.1093/emboj/18.11.3024
*cite journal | author=Paradis S, Ailion M, Toker A, "et al." |title=A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. |journal=Genes Dev. |volume=13 |issue= 11 |pages= 1438–52 |year= 1999 |pmid= 10364160 |doi=
*cite journal | author=Casamayor A, Morrice NA, Alessi DR |title=Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. |journal=Biochem. J. |volume=342 ( Pt 2) |issue= |pages= 287–92 |year= 1999 |pmid= 10455013 |doi=

External links

*EC number|2.7.11.1
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