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In the field of biochemistry, 3-phosphoinositide dependent protein kinase-1, also known as PDPK1 is a protein which in humans is encoded by the PDPK1 gene.[1]
PDPK1 is also known as "PDK1" ("PDK" can be confused with pyruvate dehydrogenase kinase.)
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Function
PDPK1 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 PDPK1 is in the signalling pathways activated by several growth factors and hormones including insulin signalling. Mice lacking PDPK1 die during early embryonic development, indicating that this enzyme is critical for transmitting the growth-promoting signals nescessary for normal mammalian development. Mice that are deficient in PDPK1 have a ≈40% decrease in body mass, mild glucose intolerance, and are resistant to cancer brought about by hyperactivation of the PI3K pathway (PTEN+/-).[2][3]
Etymology
PDPK1 stands for 3-phosphoinositide-dependent protein kinase 1. PDPK1 functions downstream of PI3K through PDPK1's interaction with membrane phospholipids including phosphatidylinositols, phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. PI3K indirectly regulates PDPK1 by phosphorylating phosphatidylinositols which in turn generates phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. However, PDPK1 is believed to be constitutively 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. PDPK1 however does not require membrane lipid binding for the efficient phosphorylation of most of its substrates in the cytosol (not at the cell membrane).
Structure
The structure of PDPK1 can be divided into two domains; the kinase or catalytic domain and the PH domain. The PH domain functions mainly in the interaction of PDPK1 with phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate which is important in localization and activation of some of membrane associated PDPK1'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 PDPK1 substrates including S6K and Protein kinase C, require the binding at this docking site. Small molecule allosteric activators of PDPK1 were shown to selectively inhibit activation of substrates that require docking site interaction. These compounds do not bind to the active site and allow PDPK1 to activate other substrates that do not require docking site interaction. PDPK1 is constitutively active and at present, there is no known inhibitor proteins for PDPK1.
The activation of PDPK1's main effector, AKT, is believed to require a proper orientation of the kinase and PH domains of PDPK1 and AKT at the membrane.
Interactions
Phosphoinositide-dependent kinase-1 has been shown to interact with SGK,[4][5] PRKACA,[6] Sodium-hydrogen exchange regulatory cofactor 2,[4] PRKCD,[7] Protein kinase Mζ,[5][7][8][9] PKN2,[7][8] PRKCI,[8] Protein kinase N1,[8] YWHAH[10] and AKT1.[11][12]
References
- ^ "Entrez Gene: PDPK1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5170.
- ^ Mora A, Komander D, van Aalten DM, Alessi DR (April 2004). "PDK1, the master regulator of AGC kinase signal transduction". Semin. Cell Dev. Biol. 15 (2): 161–70. PMID 15209375.
- ^ Frödin M, Antal TL, Dümmler BA, Jensen CJ, Deak M, Gammeltoft S, Biondi RM (October 2002). "A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation". EMBO J. 21 (20): 5396–407. PMID 12374740.
- ^ a b Chun, Jaesun; Kwon Taegun, Lee Eunjung, Suh Pann-Ghill, Choi Eui-Ju, Sun Kang Sang (Oct. 2002). "The Na(+)/H(+) exchanger regulatory factor 2 mediates phosphorylation of serum- and glucocorticoid-induced protein kinase 1 by 3-phosphoinositide-dependent protein kinase 1". Biochem. Biophys. Res. Commun. (United States) 298 (2): 207–15. ISSN 0006-291X. PMID 12387817.
- ^ a b Park, J; Leong M L, Buse P, Maiyar A C, Firestone G L, Hemmings B A (Jun. 1999). "Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway". EMBO J. (ENGLAND) 18 (11): 3024–33. doi:. ISSN 0261-4189. PMID 10357815.
- ^ Biondi, R M; Cheung P C, Casamayor A, Deak M, Currie R A, Alessi D R (Mar. 2000). "Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-terminal residues of PKA". EMBO J. (ENGLAND) 19 (5): 979–88. doi:. ISSN 0261-4189. PMID 10698939.
- ^ a b c Hodgkinson, Conrad P; Sale Graham J (Jan. 2002). "Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment". Biochemistry (United States) 41 (2): 561–9. ISSN 0006-2960. PMID 11781095.
- ^ a b c d Balendran, A; Biondi R M, Cheung P C, Casamayor A, Deak M, Alessi D R (Jul. 2000). "A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase Czeta (PKCzeta ) and PKC-related kinase 2 by PDK1". J. Biol. Chem. (UNITED STATES) 275 (27): 20806–13. doi:. ISSN 0021-9258. PMID 10764742.
- ^ Le Good, J A; Ziegler W H, Parekh D B, Alessi D R, Cohen P, Parker P J (Sep. 1998). "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1". Science (UNITED STATES) 281 (5385): 2042–5. ISSN 0036-8075. PMID 9748166.
- ^ Sato, Saori; Fujita Naoya, Tsuruo Takashi (Oct. 2002). "Regulation of kinase activity of 3-phosphoinositide-dependent protein kinase-1 by binding to 14-3-3". J. Biol. Chem. (United States) 277 (42): 39360–7. doi:. ISSN 0021-9258. PMID 12177059.
- ^ Barry, Fiona A; Gibbins Jonathan M (Apr. 2002). "Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI". J. Biol. Chem. (United States) 277 (15): 12874–8. doi:. ISSN 0021-9258. PMID 11825911.
- ^ Persad, S; Attwell S, Gray V, Mawji N, Deng J T, Leung D, Yan J, Sanghera J, Walsh M P, Dedhar S (Jul. 2001). "Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343". J. Biol. Chem. (United States) 276 (29): 27462–9. doi:. ISSN 0021-9258. PMID 11313365.
Further reading
- Vanhaesebroeck B, Alessi DR (2000). "The PI3K-PDK1 connection: more than just a road to PKB.". Biochem. J. 346 Pt 3: 561–76. PMID 10698680.
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.". Gene 138 (1-2): 171–4. PMID 8125298.
- Alessi DR, James SR, Downes CP, et al. (1997). "Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha.". Curr. Biol. 7 (4): 261–9. PMID 9094314.
- Moser BA, Dennis PB, Pullen N, et al. (1997). "Dual requirement for a newly identified phosphorylation site in p70s6k.". Mol. Cell. Biol. 17 (9): 5648–55. PMID 9271440.
- Alessi DR, Deak M, Casamayor A, et al. (1998). "3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase.". Curr. Biol. 7 (10): 776–89. PMID 9368760.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.". Gene 200 (1-2): 149–56. PMID 9373149.
- Meier R, Alessi DR, Cron P, et al. (1997). "Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta.". J. Biol. Chem. 272 (48): 30491–7. PMID 9374542.
- Alessi DR, Kozlowski MT, Weng QP, et al. (1998). "3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro.". Curr. Biol. 8 (2): 69–81. PMID 9427642.
- Dalby KN, Morrice N, Caudwell FB, et al. (1998). "Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90rsk that are inducible by MAPK.". J. Biol. Chem. 273 (3): 1496–505. PMID 9430688.
- Pullen N, Dennis PB, Andjelkovic M, et al. (1998). "Phosphorylation and activation of p70s6k by PDK1.". Science 279 (5351): 707–10. PMID 9445476.
- Stephens L, Anderson K, Stokoe D, et al. (1998). "Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B.". Science 279 (5351): 710–4. PMID 9445477.
- Walker KS, Deak M, Paterson A, et al. (1998). "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.". Biochem. J. 331 ( Pt 1): 299–308. PMID 9512493.
- Anderson KE, Coadwell J, Stephens LR, Hawkins PT (1998). "Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B.". Curr. Biol. 8 (12): 684–91. PMID 9637919.
- Le Good JA, Ziegler WH, Parekh DB, et al. (1998). "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1.". Science 281 (5385): 2042–5. PMID 9748166.
- Currie RA, Walker KS, Gray A, et al. (1999). "Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1.". Biochem. J. 337 ( Pt 3): 575–83. PMID 9895304.
- Kobayashi T, Cohen P (1999). "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.". Biochem. J. 339 ( Pt 2): 319–28. PMID 10191262.
- Balendran A, Casamayor A, Deak M, et al. (1999). "PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2.". Curr. Biol. 9 (8): 393–404. PMID 10226025.
- Park J, Leong ML, Buse P, et al. (1999). "Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway.". EMBO J. 18 (11): 3024–33. doi:. PMID 10357815.
- Paradis S, Ailion M, Toker A, et al. (1999). "A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans.". Genes Dev. 13 (11): 1438–52. PMID 10364160.
- Casamayor A, Morrice NA, Alessi DR (1999). "Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo.". Biochem. J. 342 ( Pt 2): 287–92. PMID 10455013.
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