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Biochem J. May 15, 2003; 372(Pt 1): 1–13.
PMCID: PMC1223382

Signalling specificity of Ser/Thr protein kinases through docking-site-mediated interactions.

Abstract

Signal transduction pathways use protein kinases for the modification of protein function by phosphorylation. A major question in the field is how protein kinases achieve the specificity required to regulate multiple cellular functions. Here we review recent studies that illuminate the mechanisms used by three families of Ser/Thr protein kinases to achieve substrate specificity. These kinases rely on direct docking interactions with substrates, using sites distinct from the phospho-acceptor sequences. Docking interactions also contribute to the specificity and regulation of protein kinase activities. Mitogen-activated protein kinase (MAPK) family members can associate with and phosphorylate specific substrates by virtue of minor variations in their docking sequences. Interestingly, the same MAPK docking pocket that binds substrates also binds docking sequences of positive and negative MAPK regulators. In the case of glycogen synthase kinase 3 (GSK3), the presence of a phosphate-binding site allows docking of previously phosphorylated (primed) substrates; this docking site is also required for the mechanism of GSK3 inhibition by phosphorylation. In contrast, non-primed substrates interact with a different region of GSK3. Phosphoinositide-dependent protein kinase-1 (PDK1) contains a hydrophobic pocket that interacts with a hydrophobic motif present in all known substrates, enabling their efficient phosphorylation. Binding of the substrate hydrophobic motifs to the pocket in the kinase domain activates PDK1 and other members of the AGC family of protein kinases. Finally, the analysis of protein kinase structures indicates that the sites used for docking substrates can also bind N- and C-terminal extensions to the kinase catalytic core and participate in the regulation of its activity.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Hunter T, Plowman GD. The protein kinases of budding yeast: six score and more. Trends Biochem Sci. 1997 Jan;22(1):18–22. [PubMed]
  • Plowman GD, Sudarsanam S, Bingham J, Whyte D, Hunter T. The protein kinases of Caenorhabditis elegans: a model for signal transduction in multicellular organisms. Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13603–13610. [PMC free article] [PubMed]
  • Morrison DK, Murakami MS, Cleghon V. Protein kinases and phosphatases in the Drosophila genome. J Cell Biol. 2000 Jul 24;150(2):F57–F62. [PMC free article] [PubMed]
  • Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002 Dec 6;298(5600):1912–1934. [PubMed]
  • Cohen Philip. Protein kinases--the major drug targets of the twenty-first century? Nat Rev Drug Discov. 2002 Apr;1(4):309–315. [PubMed]
  • Pawson T, Nash P. Protein-protein interactions define specificity in signal transduction. Genes Dev. 2000 May 1;14(9):1027–1047. [PubMed]
  • Kemp BE, Bylund DB, Huang TS, Krebs EG. Substrate specificity of the cyclic AMP-dependent protein kinase. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3448–3452. [PMC free article] [PubMed]
  • Zetterqvist O, Ragnarsson U, Humble E, Berglund L, Engström L. The minimum substrate of cyclic AMP-stimulated protein kinase, as studied by synthetic peptides representing the phosphorylatable site of pyruvate kinase (type L) of rat liver. Biochem Biophys Res Commun. 1976 Jun 7;70(3):696–703. [PubMed]
  • Pinna LA, Ruzzene M. How do protein kinases recognize their substrates? Biochim Biophys Acta. 1996 Dec 12;1314(3):191–225. [PubMed]
  • Kemp BE, Pearson RB. Design and use of peptide substrates for protein kinases. Methods Enzymol. 1991;200:121–134. [PubMed]
  • Adler V, Franklin CC, Kraft AS. Phorbol esters stimulate the phosphorylation of c-Jun but not v-Jun: regulation by the N-terminal delta domain. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5341–5345. [PMC free article] [PubMed]
  • Kallunki T, Su B, Tsigelny I, Sluss HK, Dérijard B, Moore G, Davis R, Karin M. JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes Dev. 1994 Dec 15;8(24):2996–3007. [PubMed]
  • Lowe ED, Noble ME, Skamnaki VT, Oikonomakos NG, Owen DJ, Johnson LN. The crystal structure of a phosphorylase kinase peptide substrate complex: kinase substrate recognition. EMBO J. 1997 Nov 17;16(22):6646–6658. [PMC free article] [PubMed]
  • Chen YG, Hata A, Lo RS, Wotton D, Shi Y, Pavletich N, Massagué J. Determinants of specificity in TGF-beta signal transduction. Genes Dev. 1998 Jul 15;12(14):2144–2152. [PMC free article] [PubMed]
  • Lo RS, Chen YG, Shi Y, Pavletich NP, Massagué J. The L3 loop: a structural motif determining specific interactions between SMAD proteins and TGF-beta receptors. EMBO J. 1998 Feb 16;17(4):996–1005. [PMC free article] [PubMed]
  • Adams PD, Sellers WR, Sharma SK, Wu AD, Nalin CM, Kaelin WG., Jr Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cyclin-dependent kinase inhibitors. Mol Cell Biol. 1996 Dec;16(12):6623–6633. [PMC free article] [PubMed]
  • Schulman BA, Lindstrom DL, Harlow E. Substrate recruitment to cyclin-dependent kinase 2 by a multipurpose docking site on cyclin A. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10453–10458. [PMC free article] [PubMed]
  • Brown NR, Noble ME, Endicott JA, Johnson LN. The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases. Nat Cell Biol. 1999 Nov;1(7):438–443. [PubMed]
  • Lowe Edward D, Tews Ivo, Cheng Kin Yip, Brown Nick R, Gul Sheraz, Noble Martin E M, Gamblin Steven J, Johnson Louise N. Specificity determinants of recruitment peptides bound to phospho-CDK2/cyclin A. Biochemistry. 2002 Dec 31;41(52):15625–15634. [PubMed]
  • Sharrocks AD, Yang SH, Galanis A. Docking domains and substrate-specificity determination for MAP kinases. Trends Biochem Sci. 2000 Sep;25(9):448–453. [PubMed]
  • Tanoue Takuji, Nishida Eisuke. Docking interactions in the mitogen-activated protein kinase cascades. Pharmacol Ther. 2002 Feb-Mar;93(2-3):193–202. [PubMed]
  • Yang SH, Whitmarsh AJ, Davis RJ, Sharrocks AD. Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1. EMBO J. 1998 Mar 16;17(6):1740–1749. [PMC free article] [PubMed]
  • Tanoue T, Adachi M, Moriguchi T, Nishida E. A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat Cell Biol. 2000 Feb;2(2):110–116. [PubMed]
  • Barsyte-Lovejoy Dalia, Galanis Alex, Sharrocks Andrew D. Specificity determinants in MAPK signaling to transcription factors. J Biol Chem. 2002 Mar 22;277(12):9896–9903. [PubMed]
  • Seidel Jeffrey J, Graves Barbara J. An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors. Genes Dev. 2002 Jan 1;16(1):127–137. [PMC free article] [PubMed]
  • Jacobs D, Glossip D, Xing H, Muslin AJ, Kornfeld K. Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev. 1999 Jan 15;13(2):163–175. [PMC free article] [PubMed]
  • Fantz DA, Jacobs D, Glossip D, Kornfeld K. Docking sites on substrate proteins direct extracellular signal-regulated kinase to phosphorylate specific residues. J Biol Chem. 2001 Jul 20;276(29):27256–27265. [PubMed]
  • Murphy Leon O, Smith Sallie, Chen Rey-Huei, Fingar Diane C, Blenis John. Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol. 2002 Aug;4(8):556–564. [PubMed]
  • MacKenzie SJ, Baillie GS, McPhee I, Bolger GB, Houslay MD. ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phosphodiesterases. The involvement of COOH-terminal docking sites and NH2-terminal UCR regions. J Biol Chem. 2000 Jun 2;275(22):16609–16617. [PubMed]
  • Pulido R, Zúiga A, Ullrich A. PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif. EMBO J. 1998 Dec 15;17(24):7337–7350. [PMC free article] [PubMed]
  • Zúiga A, Torres J, Ubeda J, Pulido R. Interaction of mitogen-activated protein kinases with the kinase interaction motif of the tyrosine phosphatase PTP-SL provides substrate specificity and retains ERK2 in the cytoplasm. J Biol Chem. 1999 Jul 30;274(31):21900–21907. [PubMed]
  • Gavin AC, Nebreda AR. A MAP kinase docking site is required for phosphorylation and activation of p90(rsk)/MAPKAP kinase-1. Curr Biol. 1999 Mar 11;9(5):281–284. [PubMed]
  • Smith JA, Poteet-Smith CE, Malarkey K, Sturgill TW. Identification of an extracellular signal-regulated kinase (ERK) docking site in ribosomal S6 kinase, a sequence critical for activation by ERK in vivo. J Biol Chem. 1999 Jan 29;274(5):2893–2898. [PubMed]
  • Gavin AC, Ni Ainle A, Chierici E, Jones M, Nebreda AR. A p90(rsk) mutant constitutively interacting with MAP kinase uncouples MAP kinase from p34(cdc2)/cyclin B activation in Xenopus oocytes. Mol Biol Cell. 1999 Sep;10(9):2971–2986. [PMC free article] [PubMed]
  • Deak M, Clifton AD, Lucocq LM, Alessi DR. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 1998 Aug 3;17(15):4426–4441. [PMC free article] [PubMed]
  • Fukunaga R, Hunter T. MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J. 1997 Apr 15;16(8):1921–1933. [PMC free article] [PubMed]
  • Waskiewicz AJ, Flynn A, Proud CG, Cooper JA. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J. 1997 Apr 15;16(8):1909–1920. [PMC free article] [PubMed]
  • Pierrat B, Correia JS, Mary JL, Tomás-Zuber M, Lesslauer W. RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogen-activated protein kinase (p38alphaMAPK). J Biol Chem. 1998 Nov 6;273(45):29661–29671. [PubMed]
  • New L, Zhao M, Li Y, Bassett WW, Feng Y, Ludwig S, Padova FD, Gram H, Han J. Cloning and characterization of RLPK, a novel RSK-related protein kinase. J Biol Chem. 1999 Jan 8;274(2):1026–1032. [PubMed]
  • Smith JA, Poteet-Smith CE, Lannigan DA, Freed TA, Zoltoski AJ, Sturgill TW. Creation of a stress-activated p90 ribosomal S6 kinase. The carboxyl-terminal tail of the MAPK-activated protein kinases dictates the signal transduction pathway in which they function. J Biol Chem. 2000 Oct 13;275(41):31588–31593. [PubMed]
  • Tanoue T, Maeda R, Adachi M, Nishida E. Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions. EMBO J. 2001 Feb 1;20(3):466–479. [PMC free article] [PubMed]
  • Enslen H, Davis RJ. Regulation of MAP kinases by docking domains. Biol Cell. 2001 Sep;93(1-2):5–14. [PubMed]
  • Bardwell L, Thorner J. A conserved motif at the amino termini of MEKs might mediate high-affinity interaction with the cognate MAPKs. Trends Biochem Sci. 1996 Oct;21(10):373–374. [PubMed]
  • Enslen H, Brancho DM, Davis RJ. Molecular determinants that mediate selective activation of p38 MAP kinase isoforms. EMBO J. 2000 Mar 15;19(6):1301–1311. [PMC free article] [PubMed]
  • Alonso G, Ambrosino C, Jones M, Nebreda AR. Differential activation of p38 mitogen-activated protein kinase isoforms depending on signal strength. J Biol Chem. 2000 Dec 22;275(51):40641–40648. [PubMed]
  • Blanco-Aparicio C, Torres J, Pulido R. A novel regulatory mechanism of MAP kinases activation and nuclear translocation mediated by PKA and the PTP-SL tyrosine phosphatase. J Cell Biol. 1999 Dec 13;147(6):1129–1136. [PMC free article] [PubMed]
  • Muda M, Theodosiou A, Gillieron C, Smith A, Chabert C, Camps M, Boschert U, Rodrigues N, Davies K, Ashworth A, et al. The mitogen-activated protein kinase phosphatase-3 N-terminal noncatalytic region is responsible for tight substrate binding and enzymatic specificity. J Biol Chem. 1998 Apr 10;273(15):9323–9329. [PubMed]
  • Slack DN, Seternes OM, Gabrielsen M, Keyse SM. Distinct binding determinants for ERK2/p38alpha and JNK map kinases mediate catalytic activation and substrate selectivity of map kinase phosphatase-1. J Biol Chem. 2001 May 11;276(19):16491–16500. [PubMed]
  • Chen P, Hutter D, Yang X, Gorospe M, Davis RJ, Liu Y. Discordance between the binding affinity of mitogen-activated protein kinase subfamily members for MAP kinase phosphatase-2 and their ability to activate the phosphatase catalytically. J Biol Chem. 2001 Aug 3;276(31):29440–29449. [PubMed]
  • Masuda K, Shima H, Watanabe M, Kikuchi K. MKP-7, a novel mitogen-activated protein kinase phosphatase, functions as a shuttle protein. J Biol Chem. 2001 Oct 19;276(42):39002–39011. [PubMed]
  • Whitmarsh AJ, Davis RJ. Structural organization of MAP-kinase signaling modules by scaffold proteins in yeast and mammals. Trends Biochem Sci. 1998 Dec;23(12):481–485. [PubMed]
  • Kallunki T, Deng T, Hibi M, Karin M. c-Jun can recruit JNK to phosphorylate dimerization partners via specific docking interactions. Cell. 1996 Nov 29;87(5):929–939. [PubMed]
  • Catling AD, Schaeffer HJ, Reuter CW, Reddy GR, Weber MJ. A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function. Mol Cell Biol. 1995 Oct;15(10):5214–5225. [PMC free article] [PubMed]
  • Xia Y, Wu Z, Su B, Murray B, Karin M. JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension. Genes Dev. 1998 Nov 1;12(21):3369–3381. [PMC free article] [PubMed]
  • Camps M, Nichols A, Gillieron C, Antonsson B, Muda M, Chabert C, Boschert U, Arkinstall S. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science. 1998 May 22;280(5367):1262–1265. [PubMed]
  • Rubinfeld H, Hanoch T, Seger R. Identification of a cytoplasmic-retention sequence in ERK2. J Biol Chem. 1999 Oct 22;274(43):30349–30352. [PubMed]
  • Xu Be, Stippec S, Robinson FL, Cobb MH. Hydrophobic as well as charged residues in both MEK1 and ERK2 are important for their proper docking. J Biol Chem. 2001 Jul 13;276(28):26509–26515. [PubMed]
  • Yung Y, Yao Z, Aebersold DM, Hanoch T, Seger R. Altered regulation of ERK1b by MEK1 and PTP-SL and modified Elk1 phosphorylation by ERK1b are caused by abrogation of the regulatory C-terminal sequence of ERKs. J Biol Chem. 2001 Sep 21;276(38):35280–35289. [PubMed]
  • Bott CM, Thorneycroft SG, Marshall CJ. The sevenmaker gain-of-function mutation in p42 MAP kinase leads to enhanced signalling and reduced sensitivity to dual specificity phosphatase action. FEBS Lett. 1994 Sep 26;352(2):201–205. [PubMed]
  • Eblen ST, Catling AD, Assanah MC, Weber MJ. Biochemical and biological functions of the N-terminal, noncatalytic domain of extracellular signal-regulated kinase 2. Mol Cell Biol. 2001 Jan;21(1):249–259. [PMC free article] [PubMed]
  • Tárrega Céline, Blanco-Aparicio Carmen, Muñoz Juan José, Pulido Rafael. Two clusters of residues at the docking groove of mitogen-activated protein kinases differentially mediate their functional interaction with the tyrosine phosphatases PTP-SL and STEP. J Biol Chem. 2002 Jan 25;277(4):2629–2636. [PubMed]
  • Robinson Fred L, Whitehurst Angelique W, Raman Malavika, Cobb Melanie H. Identification of novel point mutations in ERK2 that selectively disrupt binding to MEK1. J Biol Chem. 2002 Apr 26;277(17):14844–14852. [PubMed]
  • Zhang F, Strand A, Robbins D, Cobb MH, Goldsmith EJ. Atomic structure of the MAP kinase ERK2 at 2.3 A resolution. Nature. 1994 Feb 24;367(6465):704–711. [PubMed]
  • Frame S, Cohen P. GSK3 takes centre stage more than 20 years after its discovery. Biochem J. 2001 Oct 1;359(Pt 1):1–16. [PMC free article] [PubMed]
  • Ali A, Hoeflich KP, Woodgett JR. Glycogen synthase kinase-3: properties, functions, and regulation. Chem Rev. 2001 Aug;101(8):2527–2540. [PubMed]
  • Grimes CA, Jope RS. The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol. 2001 Nov;65(4):391–426. [PubMed]
  • Kaytor Michael D, Orr Harry T. The GSK3 beta signaling cascade and neurodegenerative disease. Curr Opin Neurobiol. 2002 Jun;12(3):275–278. [PubMed]
  • Kim L, Kimmel AR. GSK3, a master switch regulating cell-fate specification and tumorigenesis. Curr Opin Genet Dev. 2000 Oct;10(5):508–514. [PubMed]
  • Manoukian Armen S, Woodgett James R. Role of glycogen synthase kinase-3 in cancer: regulation by Wnts and other signaling pathways. Adv Cancer Res. 2002;84:203–229. [PubMed]
  • Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L, et al. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol. 2000 Oct;7(10):793–803. [PubMed]
  • Cross DA, Culbert AA, Chalmers KA, Facci L, Skaper SD, Reith AD. Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J Neurochem. 2001 Apr;77(1):94–102. [PubMed]
  • Welsh GI, Proud CG. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J. 1993 Sep 15;294(Pt 3):625–629. [PMC free article] [PubMed]
  • Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995 Dec 21;378(6559):785–789. [PubMed]
  • Fiol CJ, Mahrenholz AM, Wang Y, Roeske RW, Roach PJ. Formation of protein kinase recognition sites by covalent modification of the substrate. Molecular mechanism for the synergistic action of casein kinase II and glycogen synthase kinase 3. J Biol Chem. 1987 Oct 15;262(29):14042–14048. [PubMed]
  • Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell. 2001 Jun;7(6):1321–1327. [PubMed]
  • Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH. Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell. 2001 Jun 15;105(6):721–732. [PubMed]
  • ter Haar E, Coll JT, Austen DA, Hsiao HM, Swenson L, Jain J. Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat Struct Biol. 2001 Jul;8(7):593–596. [PubMed]
  • Moon Randall T, Bowerman Bruce, Boutros Michael, Perrimon Norbert. The promise and perils of Wnt signaling through beta-catenin. Science. 2002 May 31;296(5573):1644–1646. [PubMed]
  • Polakis P. More than one way to skin a catenin. Cell. 2001 Jun 1;105(5):563–566. [PubMed]
  • Seidensticker MJ, Behrens J. Biochemical interactions in the wnt pathway. Biochim Biophys Acta. 2000 Feb 2;1495(2):168–182. [PubMed]
  • Farr GH, 3rd, Ferkey DM, Yost C, Pierce SB, Weaver C, Kimelman D. Interaction among GSK-3, GBP, axin, and APC in Xenopus axis specification. J Cell Biol. 2000 Feb 21;148(4):691–702. [PMC free article] [PubMed]
  • Li L, Yuan H, Weaver CD, Mao J, Farr GH, 3rd, Sussman DJ, Jonkers J, Kimelman D, Wu D. Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. EMBO J. 1999 Aug 2;18(15):4233–4240. [PMC free article] [PubMed]
  • Behrens J, Jerchow BA, Würtele M, Grimm J, Asbrand C, Wirtz R, Kühl M, Wedlich D, Birchmeier W. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science. 1998 Apr 24;280(5363):596–599. [PubMed]
  • Ding VW, Chen RH, McCormick F. Differential regulation of glycogen synthase kinase 3beta by insulin and Wnt signaling. J Biol Chem. 2000 Oct 20;275(42):32475–32481. [PubMed]
  • Hagen Thilo, Vidal-Puig Antonio. Characterisation of the phosphorylation of beta-catenin at the GSK-3 priming site Ser45. Biochem Biophys Res Commun. 2002 Jun 7;294(2):324–328. [PubMed]
  • Hagen Thilo, Di Daniel Elena, Culbert Ainsley A, Reith Alastair D. Expression and characterization of GSK-3 mutants and their effect on beta-catenin phosphorylation in intact cells. J Biol Chem. 2002 Jun 28;277(26):23330–23335. [PubMed]
  • Toker A, Newton AC. Cellular signaling: pivoting around PDK-1. Cell. 2000 Oct 13;103(2):185–188. [PubMed]
  • Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J. 2000 Mar 15;346(Pt 3):561–576. [PMC free article] [PubMed]
  • Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science. 1997 Jul 25;277(5325):567–570. [PubMed]
  • Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997 Apr 1;7(4):261–269. [PubMed]
  • Leslie NR, Biondi RM, Alessi DR. Phosphoinositide-regulated kinases and phosphoinositide phosphatases. Chem Rev. 2001 Aug;101(8):2365–2380. [PubMed]
  • Moore Michael J, Kanter Joan R, Jones KC, Taylor Susan S. Phosphorylation of the catalytic subunit of protein kinase A. Autophosphorylation versus phosphorylation by phosphoinositide-dependent kinase-1. J Biol Chem. 2002 Dec 6;277(49):47878–47884. [PubMed]
  • Flynn P, Wongdagger M, Zavar M, Dean NM, Stokoe D. Inhibition of PDK-1 activity causes a reduction in cell proliferation and survival. Curr Biol. 2000 Nov 16;10(22):1439–1442. [PubMed]
  • Williams MR, Arthur JS, Balendran A, van der Kaay J, Poli V, Cohen P, Alessi DR. The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells. Curr Biol. 2000 Apr 20;10(8):439–448. [PubMed]
  • Biondi RM, Cheung PC, Casamayor A, Deak M, Currie RA, Alessi DR. Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-terminal residues of PKA. EMBO J. 2000 Mar 1;19(5):979–988. [PMC free article] [PubMed]
  • Frödin M, Jensen CJ, Merienne K, Gammeltoft S. A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1. EMBO J. 2000 Jun 15;19(12):2924–2934. [PMC free article] [PubMed]
  • Chen H, Nystrom FH, Dong LQ, Li Y, Song S, Liu F, Quon MJ. Insulin stimulates increased catalytic activity of phosphoinositide-dependent kinase-1 by a phosphorylation-dependent mechanism. Biochemistry. 2001 Oct 2;40(39):11851–11859. [PubMed]
  • Park J, Hill MM, Hess D, Brazil DP, Hofsteenge J, Hemmings BA. Identification of tyrosine phosphorylation sites on 3-phosphoinositide-dependent protein kinase-1 and their role in regulating kinase activity. J Biol Chem. 2001 Oct 5;276(40):37459–37471. [PubMed]
  • Dong LQ, Zhang RB, Langlais P, He H, Clark M, Zhu L, Liu F. Primary structure, tissue distribution, and expression of mouse phosphoinositide-dependent protein kinase-1, a protein kinase that phosphorylates and activates protein kinase Czeta. J Biol Chem. 1999 Mar 19;274(12):8117–8122. [PubMed]
  • Belham C, Wu S, Avruch J. Intracellular signalling: PDK1--a kinase at the hub of things. Curr Biol. 1999 Feb 11;9(3):R93–R96. [PubMed]
  • Dutil EM, Toker A, Newton AC. Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1). Curr Biol. 1998 Dec 17;8(25):1366–1375. [PubMed]
  • Romanelli A, Martin KA, Toker A, Blenis J. p70 S6 kinase is regulated by protein kinase Czeta and participates in a phosphoinositide 3-kinase-regulated signalling complex. Mol Cell Biol. 1999 Apr;19(4):2921–2928. [PMC free article] [PubMed]
  • Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ. Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science. 1998 Sep 25;281(5385):2042–2045. [PubMed]
  • 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. [PubMed]
  • Koh H, Lee KH, Kim D, Kim S, Kim JW, Chung J. Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage. J Biol Chem. 2000 Nov 3;275(44):34451–34458. [PubMed]
  • Yang Jing, Cron Peter, Thompson Vivienne, Good Valerie M, Hess Daniel, Hemmings Brian A, Barford David. Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol Cell. 2002 Jun;9(6):1227–1240. [PubMed]
  • Yang Jing, Cron Peter, Good Valerie M, Thompson Vivienne, Hemmings Brian A, Barford David. Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nat Struct Biol. 2002 Dec;9(12):940–944. [PubMed]
  • Gao T, Toker A, Newton AC. The carboxyl terminus of protein kinase c provides a switch to regulate its interaction with the phosphoinositide-dependent kinase, PDK-1. J Biol Chem. 2001 Jun 1;276(22):19588–19596. [PubMed]
  • Newton AC. Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev. 2001 Aug;101(8):2353–2364. [PubMed]
  • Balendran A, Biondi RM, Cheung PC, Casamayor A, Deak M, Alessi DR. 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. 2000 Jul 7;275(27):20806–20813. [PubMed]
  • Biondi RM, Kieloch A, Currie RA, Deak M, Alessi DR. The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. EMBO J. 2001 Aug 15;20(16):4380–4390. [PMC free article] [PubMed]
  • Flynn P, Mellor H, Casamassima A, Parker PJ. Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase. J Biol Chem. 2000 Apr 14;275(15):11064–11070. [PubMed]
  • Weng QP, Andrabi K, Kozlowski MT, Grove JR, Avruch J. Multiple independent inputs are required for activation of the p70 S6 kinase. Mol Cell Biol. 1995 May;15(5):2333–2340. [PMC free article] [PubMed]
  • Dennis PB, Pullen N, Pearson RB, Kozma SC, Thomas G. Phosphorylation sites in the autoinhibitory domain participate in p70(s6k) activation loop phosphorylation. J Biol Chem. 1998 Jun 12;273(24):14845–14852. [PubMed]
  • Anderson KE, Coadwell J, Stephens LR, Hawkins PT. Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B. Curr Biol. 1998 Jun 4;8(12):684–691. [PubMed]
  • Filippa N, Sable CL, Hemmings BA, Van Obberghen E. Effect of phosphoinositide-dependent kinase 1 on protein kinase B translocation and its subsequent activation. Mol Cell Biol. 2000 Aug;20(15):5712–5721. [PMC free article] [PubMed]
  • Balendran A, Currie R, Armstrong CG, Avruch J, Alessi DR. Evidence that 3-phosphoinositide-dependent protein kinase-1 mediates phosphorylation of p70 S6 kinase in vivo at Thr-412 as well as Thr-252. J Biol Chem. 1999 Dec 24;274(52):37400–37406. [PubMed]
  • Scheid Michael P, Marignani Paola A, Woodgett James R. Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol Cell Biol. 2002 Sep;22(17):6247–6260. [PMC free article] [PubMed]
  • Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science. 1991 Jul 26;253(5018):407–414. [PubMed]
  • Batkin M, Schvartz I, Shaltiel S. Snapping of the carboxyl terminal tail of the catalytic subunit of PKA onto its core: characterization of the sites by mutagenesis. Biochemistry. 2000 May 9;39(18):5366–5373. [PubMed]
  • Etchebehere LC, Van Bemmelen MX, Anjard C, Traincard F, Assemat K, Reymond C, Véron M. The catalytic subunit of Dictyostelium cAMP-dependent protein kinase -- role of the N-terminal domain and of the C-terminal residues in catalytic activity and stability. Eur J Biochem. 1997 Sep 15;248(3):820–826. [PubMed]
  • Frödin Morten, Antal Torben L, Dümmler Bettina A, Jensen Claus J, Deak Maria, Gammeltoft Steen, Biondi Ricardo M. A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation. EMBO J. 2002 Oct 15;21(20):5396–5407. [PMC free article] [PubMed]
  • Pearl Laurence H, Barford David. Regulation of protein kinases in insulin, growth factor and Wnt signalling. Curr Opin Struct Biol. 2002 Dec;12(6):761–767. [PubMed]
  • Knighton DR, Xuong NH, Taylor SS, Sowadski JM. Crystallization studies of cAMP-dependent protein kinase. Cocrystals of the catalytic subunit with a 20 amino acid residue peptide inhibitor and MgATP diffract to 3.0 A resolution. J Mol Biol. 1991 Jul 20;220(2):217–220. [PubMed]
  • Johnson LN, Lowe ED, Noble ME, Owen DJ. The Eleventh Datta Lecture. The structural basis for substrate recognition and control by protein kinases. FEBS Lett. 1998 Jun 23;430(1-2):1–11. [PubMed]
  • Veron M, Radzio-Andzelm E, Tsigelny I, Ten Eyck LF, Taylor SS. A conserved helix motif complements the protein kinase core. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10618–10622. [PMC free article] [PubMed]
  • Herberg FW, Zimmermann B, McGlone M, Taylor SS. Importance of the A-helix of the catalytic subunit of cAMP-dependent protein kinase for stability and for orienting subdomains at the cleft interface. Protein Sci. 1997 Mar;6(3):569–579. [PMC free article] [PubMed]
  • Dammann H, Traincard F, Anjard C, van Bemmelen MX, Reymond C, Véron M. Functional analysis of the catalytic subunit of Dictyostelium PKA in vivo. Mech Dev. 1998 Mar;72(1-2):149–157. [PubMed]
  • Kemp BE, Parker MW, Hu S, Tiganis T, House C. Substrate and pseudosubstrate interactions with protein kinases: determinants of specificity. Trends Biochem Sci. 1994 Nov;19(11):440–444. [PubMed]
  • Chang Chung I, Xu Bing-e, Akella Radha, Cobb Melanie H, Goldsmith Elizabeth J. Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b. Mol Cell. 2002 Jun;9(6):1241–1249. [PubMed]
  • Johnson LN, Noble ME, Owen DJ. Active and inactive protein kinases: structural basis for regulation. Cell. 1996 Apr 19;85(2):149–158. [PubMed]
  • Huse Morgan, Kuriyan John. The conformational plasticity of protein kinases. Cell. 2002 May 3;109(3):275–282. [PubMed]
  • Bax B, Carter PS, Lewis C, Guy AR, Bridges A, Tanner R, Pettman G, Mannix C, Culbert AA, Brown MJ, et al. The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation. Structure. 2001 Dec;9(12):1143–1152. [PubMed]
  • Fraser Elizabeth, Young Neville, Dajani Rana, Franca-Koh Jonathan, Ryves Jonathan, Williams Robin S B, Yeo Margaret, Webster Marie-Therese, Richardson Chris, Smalley Matthew J, et al. Identification of the Axin and Frat binding region of glycogen synthase kinase-3. J Biol Chem. 2002 Jan 18;277(3):2176–2185. [PubMed]
  • Ferkey Denise M, Kimelman David. Glycogen synthase kinase-3 beta mutagenesis identifies a common binding domain for GBP and Axin. J Biol Chem. 2002 May 3;277(18):16147–16152. [PubMed]
  • Delaney Amy M, Printen John A, Chen Huifen, Fauman Eric B, Dudley David T. Identification of a novel mitogen-activated protein kinase kinase activation domain recognized by the inhibitor PD 184352. Mol Cell Biol. 2002 Nov;22(21):7593–7602. [PMC free article] [PubMed]
  • Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massagué J, Pavletich NP. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature. 1995 Jul 27;376(6538):313–320. [PubMed]
  • Card GL, Knowles P, Laman H, Jones N, McDonald NQ. Crystal structure of a gamma-herpesvirus cyclin-cdk complex. EMBO J. 2000 Jun 15;19(12):2877–2888. [PMC free article] [PubMed]

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