| Structural highlights
Function
[PDPK1_HUMAN] Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
Publication Abstract from PubMed
Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1-5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems.
Genetic and pharmacological inhibition of PDK1 in cancer cells: characterization of a selective allosteric kinase inhibitor.,Nagashima K, Shumway SD, Sathyanarayanan S, Chen AH, Dolinski B, Xu Y, Keilhack H, Nguyen T, Wiznerowicz M, Li L, Lutterbach BA, Chi A, Paweletz C, Allison T, Yan Y, Munshi SK, Klippel A, Kraus M, Bobkova EV, Deshmukh S, Xu Z, Mueller U, Szewczak AA, Pan BS, Richon V, Pollock R, Blume-Jensen P, Northrup A, Andersen JN J Biol Chem. 2011 Feb 25;286(8):6433-48. Epub 2010 Nov 30. PMID:21118801[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Chou MM, Hou W, Johnson J, Graham LK, Lee MH, Chen CS, Newton AC, Schaffhausen BS, Toker A. Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Curr Biol. 1998 Sep 24;8(19):1069-77. PMID:9768361
- ↑ Cheng X, Ma Y, Moore M, Hemmings BA, Taylor SS. Phosphorylation and activation of cAMP-dependent protein kinase by phosphoinositide-dependent protein kinase. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9849-54. PMID:9707564
- ↑ Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G. Phosphorylation and activation of p70s6k by PDK1. Science. 1998 Jan 30;279(5351):707-10. PMID:9445476
- ↑ Jensen CJ, Buch MB, Krag TO, Hemmings BA, Gammeltoft S, Frodin M. 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. J Biol Chem. 1999 Sep 17;274(38):27168-76. PMID:10480933
- ↑ King CC, Gardiner EM, Zenke FT, Bohl BP, Newton AC, Hemmings BA, Bokoch GM. p21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). J Biol Chem. 2000 Dec 29;275(52):41201-9. PMID:10995762 doi:10.1074/jbc.M006553200
- ↑ Scheid MP, Marignani PA, Woodgett JR. Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol Cell Biol. 2002 Sep;22(17):6247-60. PMID:12167717
- ↑ Taniyama Y, Weber DS, Rocic P, Hilenski L, Akers ML, Park J, Hemmings BA, Alexander RW, Griendling KK. Pyk2- and Src-dependent tyrosine phosphorylation of PDK1 regulates focal adhesions. Mol Cell Biol. 2003 Nov;23(22):8019-29. PMID:14585963
- ↑ Nilsen T, Slagsvold T, Skjerpen CS, Brech A, Stenmark H, Olsnes S. Peroxisomal targeting as a tool for assaying potein-protein interactions in the living cell: cytokine-independent survival kinase (CISK) binds PDK-1 in vivo in a phosphorylation-dependent manner. J Biol Chem. 2004 Feb 6;279(6):4794-801. Epub 2003 Nov 6. PMID:14604990 doi:10.1074/jbc.M309653200
- ↑ Balendran A, Casamayor A, Deak M, Paterson A, Gaffney P, Currie R, Downes CP, Alessi DR. PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Curr Biol. 1999 Apr 22;9(8):393-404. PMID:10226025
- ↑ Tanaka H, Fujita N, Tsuruo T. 3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase beta (IkkB) phosphorylation activates NF-kappaB signaling. J Biol Chem. 2005 Dec 9;280(49):40965-73. Epub 2005 Oct 5. PMID:16207722 doi:10.1074/jbc.M506235200
- ↑ Seong HA, Jung H, Choi HS, Kim KT, Ha H. Regulation of transforming growth factor-beta signaling and PDK1 kinase activity by physical interaction between PDK1 and serine-threonine kinase receptor-associated protein. J Biol Chem. 2005 Dec 30;280(52):42897-908. Epub 2005 Oct 26. PMID:16251192 doi:10.1074/jbc.M507539200
- ↑ Seong HA, Jung H, Kim KT, Ha H. 3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins. J Biol Chem. 2007 Apr 20;282(16):12272-89. Epub 2007 Feb 27. PMID:17327236 doi:10.1074/jbc.M609279200
- ↑ Primo L, di Blasio L, Roca C, Droetto S, Piva R, Schaffhausen B, Bussolino F. Essential role of PDK1 in regulating endothelial cell migration. J Cell Biol. 2007 Mar 26;176(7):1035-47. Epub 2007 Mar 19. PMID:17371830 doi:10.1083/jcb.200607053
- ↑ Lim WG, Chen X, Liu JP, Tan BJ, Zhou S, Smith A, Lees N, Hou L, Gu F, Yu XY, Du Y, Smith D, Verma C, Liu K, Duan W. The C-terminus of PRK2/PKNgamma is required for optimal activation by RhoA in a GTP-dependent manner. Arch Biochem Biophys. 2008 Nov 15;479(2):170-8. doi: 10.1016/j.abb.2008.09.008., Epub 2008 Sep 22. PMID:18835241 doi:10.1016/j.abb.2008.09.008
- ↑ Nagashima K, Shumway SD, Sathyanarayanan S, Chen AH, Dolinski B, Xu Y, Keilhack H, Nguyen T, Wiznerowicz M, Li L, Lutterbach BA, Chi A, Paweletz C, Allison T, Yan Y, Munshi SK, Klippel A, Kraus M, Bobkova EV, Deshmukh S, Xu Z, Mueller U, Szewczak AA, Pan BS, Richon V, Pollock R, Blume-Jensen P, Northrup A, Andersen JN. Genetic and pharmacological inhibition of PDK1 in cancer cells: characterization of a selective allosteric kinase inhibitor. J Biol Chem. 2011 Feb 25;286(8):6433-48. Epub 2010 Nov 30. PMID:21118801 doi:10.1074/jbc.M110.156463
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