Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The nuts and bolts of AGC protein kinases

Nature Reviews Molecular Cell Biology volume 11, pages 9–22 (2010)Cite this article

Subjects

Key Points

  • There are 60 members of the AGC family of protein kinases, which all share a conserved catalytic kinase domain.

  • Structural studies have revealed that although the structures of active AGC kinases are highly similar, inactive AGC kinases can adopt several conformations. Most described structures to date are of the catalytic domain; further work is required to elucidate the structure of full length AGC kinases.

  • AGC family members are regulated in various ways, but most require phosphorylation and/or conformational changes to be activated.

  • Functional domains, other than the kinase domain, have important roles in regulating the activity and localization of AGC kinases. The functions of some of these domains have not been fully defined.

  • AGC kinases are involved in numerous cellular processes, exemplified by the large number of proteins that they can phosphorylate. Some substrates are phosphorylated only by one AGC kinase, whereas others can be phosphorylated by multiple AGC kinases.

  • Several AGC family members have been implicated in disease, and numerous drugs targeting these kinases have been developed to treat conditions such as cancer and diabetes. In addition mutations in certain AGC kinases are linked to some inherited syndromes.

Abstract

The AGC kinase subfamily of protein kinases contains 60 members, including PKA, PKG and PKC. The family comprises some intensely examined protein kinases (such as Akt, S6K, RSK, MSK, PDK1 and GRK) as well as many less well-studied enzymes (such as SGK, NDR, LATS, CRIK, SGK494, PRKX, PRKY and MAST). Research has shed new light onto the architecture and regulatory mechanisms of these kinases. In addition, AGC kinases mediate diverse and important cellular functions, and their mutation and/or dysregulation contributes to the pathogenesis of many human diseases, including cancer and diabetes.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Domain structures of AGC kinases.
Figure 2: Key structural features of AGC kinases.
Figure 3: Mechanisms of activation of Akt, S6K, PKC, MSK and RSK.
Figure 4: Mechanisms of activation of PKA, GRK, LATS and ROCK.
Figure 5: Roles of AGC kinases in cancer and diabetes.

Similar content being viewed by others

References

  1. Hanks, S. K. & Hunter, T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576–596 (1995).

    CAS  PubMed  Google Scholar 

  2. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002). Key paper grouping all the known members of the human kinome, including the AGC family of kinases.

    CAS  PubMed  Google Scholar 

  3. Knighton, D. R. et al. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253, 407–414 (1991).

    CAS  PubMed  Google Scholar 

  4. Johnson, L. N., Noble, M. E. & Owen, D. J. Active and inactive protein kinases: structural basis for regulation. Cell 85, 149–158 (1996).

    CAS  PubMed  Google Scholar 

  5. Yang, J. et al. Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol. Cell 9, 1227–1240 (2002).

    CAS  PubMed  Google Scholar 

  6. Komander, D., Kular, G., Deak, M., Alessi, D. R. & van Aalten, D. M. Role of T-loop phosphorylation in PDK1 activation, stability and substrate binding. J. Biol. Chem. 280, 18797–18802 (2005).

    CAS  PubMed  Google Scholar 

  7. Biondi, R. M. et al. High resolution crystal structure of the human PDK1 catalytic domain defines the regulatory phosphopeptide docking site. EMBO J. 21, 4219–4228 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Yang, J. et al. Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nature Struct. Biol. 9, 940–944 (2002).

    CAS  PubMed  Google Scholar 

  9. Hauge, C. et al. Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation. EMBO J. 26, 2251–2261 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Grodsky, N. et al. Structure of the catalytic domain of human protein kinase C β II complexed with a bisindolylmaleimide inhibitor. Biochemistry 45, 13970–13981 (2006).

    CAS  PubMed  Google Scholar 

  11. Komander, D., Garg, R., Wan, P. T., Ridley, A. J. & Barford, D. Mechanism of multi-site phosphorylation from a ROCK-I:RhoE complex structure. EMBO J. 27, 3175–3185 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Smith, K. J. et al. The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein. Structure 12, 1067–1077 (2004).

    CAS  PubMed  Google Scholar 

  13. Sunami, T. et al. Structural basis of human p70 ribosomal S6 kinase-1 regulation by activation loop phosphorylation. J. Biol. Chem. 28 Oct 2009 (doi: 10.1074/jbc.M109.040667).

    Google Scholar 

  14. Tesmer, V. M., Kawano, T., Shankaranarayanan, A., Kozasa, T. & Tesmer, J. J. Snapshot of activated G proteins at the membrane: the Gαq-GRK2-Gβγ complex. Science 310, 1686–1690 (2005).

    CAS  PubMed  Google Scholar 

  15. Currie, R. A. et al. Role of phosphatidylinositol 3, 4, 5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem. J. 337, 575–583 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Calleja, V. et al. Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo. PLoS Biol. 5, e95 (2007).

    PubMed  PubMed Central  Google Scholar 

  17. Alessi, D. R. et al. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr. Biol. 7, 776–789 (1997).

    CAS  PubMed  Google Scholar 

  18. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005). Key paper showing that mTORC2 was the elusive PDK2, which was the missing link in the PI3K pathway.

    CAS  PubMed  Google Scholar 

  19. Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22 (2007).

    CAS  PubMed  Google Scholar 

  20. Ikenoue, T., Inoki, K., Yang, Q., Zhou, X. & Guan, K. L. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 27, 1919–1931 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Facchinetti, V. et al. The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase, C. EMBOJ. 27, 1932–1943 (2008).

    CAS  Google Scholar 

  22. Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189 (2002).

    CAS  PubMed  Google Scholar 

  23. Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).

    CAS  PubMed  Google Scholar 

  24. Garcia-Martinez, J. M. & Alessi, D. R. mTOR complex-2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum and glucocorticoid induced protein kinase-1 (SGK1). Biochem. J. 416, 375–385 (2008).

    CAS  PubMed  Google Scholar 

  25. Nicklin, P. et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521–534 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nature Cell Biol. 10, 935–945 (2008).

    CAS  PubMed  Google Scholar 

  28. Findlay, G. M., Yan, L., Procter, J., Mieulet, V. & Lamb, R. F. A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling. Biochem. J. 403, 13–20 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).

    CAS  PubMed  Google Scholar 

  30. Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Biondi, R. M., Kieloch, A., Currie, R. A., Deak, M. & Alessi, D. R. The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. EMBO J. 20, 4380–4390 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Collins, B. J., Deak, M., Arthur, J. S., Armit, L. J. & Alessi, D. R. In vivo role of the PIF-binding docking site of PDK1 defined by knock-in mutation. EMBO J. 22, 4202–4211 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Tessier, M. & Woodgett, J. R. Role of the Phox homology domain and phosphorylation in activation of serum and glucocorticoid-regulated kinase-3. J. Biol. Chem. 281, 23978–23989 (2006).

    CAS  PubMed  Google Scholar 

  34. Loffing, J., Flores, S. Y. & Staub, O. Sgk kinases and their role in epithelial transport. Annu. Rev. Physiol. 68, 461–490 (2006).

    CAS  PubMed  Google Scholar 

  35. Newton, A. C. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem. J. 370, 361–371 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Le Good, J. A. et al. Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science 281, 2042–2045 (1998).

    CAS  PubMed  Google Scholar 

  37. Dutil, E. M., Toker, A. & Newton, A. C. Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1). Curr. Biol. 8, 1366–1375 (1998).

    CAS  PubMed  Google Scholar 

  38. Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).

    CAS  PubMed  Google Scholar 

  39. Guertin, D. A. et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1. Dev. Cell 11, 859–871 (2006).

    CAS  PubMed  Google Scholar 

  40. House, C. & Kemp, B. E. Protein kinase C contains a pseudosubstrate prototope in its regulatory domain. Science 238, 1726–1728 (1987).

    CAS  PubMed  Google Scholar 

  41. Balendran, A. et al. A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase Cζ (PKCζ) and PKC-related kinase 2 by PDK1. J. Biol. Chem. 275, 20806–20813 (2000).

    CAS  PubMed  Google Scholar 

  42. Biondi, R. M. et al. Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-terminal residues of PKA. EMBO J. 19, 979–988 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Flynn, P., Mellor, H., Casamassima, A. & Parker, P. J. Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase. J. Biol. Chem. 275, 11064–11070 (2000).

    CAS  PubMed  Google Scholar 

  44. Dalby, K. N., Morrice, N., Caudwell, F. B., Avruch, J. & Cohen, P. 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, 1496–1505 (1998).

    CAS  PubMed  Google Scholar 

  45. Deak, M., Clifton, A. D., Lucocq, L. M. & Alessi, D. R. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 17, 4426–4441 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Anjum, R. & Blenis, J. The RSK family of kinases: emerging roles in cellular signalling. Nature Rev. Mol. Cell Biol. 9, 747–758 (2008).

    CAS  Google Scholar 

  47. Frodin, M., Jensen, C. J., Merienne, K. & Gammeltoft, S. A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1. EMBO J. 19, 2924–2934 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Williams, M. R. et al. The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells. Curr. Biol. 10, 439–448 (2000).

    CAS  PubMed  Google Scholar 

  49. Arthur, J. S. MSK activation and physiological roles. Front. Biosci. 13, 5866–5879 (2008).

    CAS  PubMed  Google Scholar 

  50. Zaru, R., Ronkina, N., Gaestel, M., Arthur, J. S. & Watts, C. The MAPK-activated kinase Rsk controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways. Nature Immunol. 8, 1227–1235 (2007).

    CAS  Google Scholar 

  51. Ananieva, O. et al. The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nature Immunol. 9, 1028–1036 (2008). Important study showing a new role for the MSK isoforms, which raises the possibility that MSK activators could be useful as anti-inflammatory agents.

    CAS  Google Scholar 

  52. Bayascas, J. R. et al. Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. Mol. Cell. Biol 28, 3258–3272 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. King, C. C. & Newton, A. C. The adaptor protein Grb14 regulates the localization of 3-phosphoinositide-dependent kinase-1. J. Biol. Chem. 279, 37518–37527 (2004).

    CAS  PubMed  Google Scholar 

  54. Nakamura, A., Naito, M., Tsuruo, T. & Fujita, N. Freud-1/Aki1, a novel PDK1-interacting protein, functions as a scaffold to activate the PDK1/Akt pathway in epidermal growth factor signaling. Mol. Cell. Biol. 28, 5996–6009 (2008). Shows that FREUD1 can function as an important scaffold for PDK1 signalling and is required for Akt activation downstream of epidermal growth factor.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Yang, W. L. et al. The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325, 1134–1138 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Casamayor, A., Morrice, N. & Alessi, D. R. Phosphorylation of Ser 241 is essential for the activity of PDK1; identification of five sites of phosphorylation in vivo. Biochem. J. 342, 287–292 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Komander, D. et al. Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates. EMBO J. 23, 3918–3928 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Michel, J. J. et al. Spatial restriction of PDK1 activation cascades by anchoring to mAKAPα. Mol. Cell 20, 661–672 (2005).

    CAS  PubMed  Google Scholar 

  59. Lim, M. A., Kikani, C. K., Wick, M. J. & Dong, L. Q. Nuclear translocation of 3′-phosphoinositide-dependent protein kinase 1 (PDK-1): a potential regulatory mechanism for PDK-1 function. Proc. Natl Acad. Sci USA 100, 14006–14011 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Scheid, M. P., Parsons, M. & Woodgett, J. R. Phosphoinositide-dependent phosphorylation of PDK1 regulates nuclear translocation. Mol. Cell. Biol. 25, 2347–2363 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Taylor, S. S., Buechler, J. A. & Yonemoto, W. cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. Annu. Rev. Biochem. 59, 971–1005 (1990).

    CAS  PubMed  Google Scholar 

  62. Yonemoto, W., McGlone, M. L., Grant, B. & Taylor, S. S. Autophosphorylation of the catalytic subunit of cAMP-dependent protein kinase in Escherichia coli. Protein Eng. 10, 915–925 (1997).

    CAS  PubMed  Google Scholar 

  63. Cheng, X., Ma, Y., Moore, M., Hemmings, B. A. & Taylor, S. S. Phosphorylation and activation of cAMP-dependent protein kinase by phosphoinositide-dependent protein kinase. Proc. Natl Acad. Sci. USA 95, 9849–9854 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Nirula, A., Ho, M., Phee, H., Roose, J. & Weiss, A. Phosphoinositide-dependent kinase 1 targets protein kinase A in a pathway that regulates interleukin 4. J. Exp. Med. 203, 1733–1744 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Shaywitz, A. J. & Greenberg, M. E. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu. Rev. Biochem. 68, 821–861 (1999).

    CAS  PubMed  Google Scholar 

  66. Frey, U., Huang, Y. Y. & Kandel, E. R. Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science 260, 1661–1664 (1993).

    CAS  PubMed  Google Scholar 

  67. Wong, W. & Scott, J. D. AKAP signalling complexes: focal points in space and time. Nature Rev. Mol. Cell Biol. 5, 959–970 (2004).

    CAS  Google Scholar 

  68. Zimmermann, B., Chiorini, J. A., Ma, Y., Kotin, R. M. & Herberg, F. W. PrKX is a novel catalytic subunit of the cAMP-dependent protein kinase regulated by the regulatory subunit type I. J. Biol. Chem. 274, 5370–5378 (1999).

    CAS  PubMed  Google Scholar 

  69. Lucas, K. A. et al. Guanylyl cyclases and signaling by cyclic GMP. Pharmacol. Rev. 52, 375–414 (2000).

    CAS  PubMed  Google Scholar 

  70. Browning, D. D., McShane, M. P., Marty, C. & Ye, R. D. Nitric oxide activation of p38 mitogen-activated protein kinase in 293T fibroblasts requires cGMP-dependent protein kinase. J. Biol. Chem. 275, 2811–2816 (2000).

    CAS  PubMed  Google Scholar 

  71. Zhuo, M., Hu, Y., Schultz, C., Kandel, E. R. & Hawkins, R. D. Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation. Nature 368, 635–639 (1994).

    CAS  PubMed  Google Scholar 

  72. Pitcher, J. A., Freedman, N. J. & Lefkowitz, R. J. G protein-coupled receptor kinases. Annu. Rev. Biochem. 67, 653–692 (1998).

    CAS  PubMed  Google Scholar 

  73. Li, J. et al. Agonist-induced formation of opioid receptor-G protein-coupled receptor kinase (GRK)-G β γ complex on membrane is required for GRK2 function in vivo. J. Biol. Chem. 278, 30219–30226 (2003).

    CAS  PubMed  Google Scholar 

  74. Cong, M. et al. Regulation of membrane targeting of the G protein-coupled receptor kinase 2 by protein kinase A and its anchoring protein AKAP79. J. Biol. Chem. 276, 15192–15199 (2001).

    CAS  PubMed  Google Scholar 

  75. Pitcher, J. A. et al. Feedback inhibition of G protein-coupled receptor kinase 2 (GRK2) activity by extracellular signal-regulated kinases. J. Biol. Chem. 274, 34531–34534 (1999).

    CAS  PubMed  Google Scholar 

  76. Pronin, A. N., Carman, C. V. & Benovic, J. L. Structure-function analysis of G protein-coupled receptor kinase-5. Role of the carboxyl terminus in kinase regulation. J. Biol. Chem. 273, 31510–31518 (1998).

    CAS  PubMed  Google Scholar 

  77. Hergovich, A., Cornils, H. & Hemmings, B. A. Mammalian NDR protein kinases: from regulation to a role in centrosome duplication. Biochim. Biophys. Acta 1784, 3–15 (2008).

    CAS  PubMed  Google Scholar 

  78. Zhao, B., Lei, Q. Y. & Guan, K. L. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr. Opin. Cell Biol. 20, 638–646 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Devroe, E., Erdjument-Bromage, H., Tempst, P. & Silver, P. A. Human Mob proteins regulate the NDR1 and NDR2 serine-threonine kinases. J. Biol. Chem. 279, 24444–24451 (2004).

    CAS  PubMed  Google Scholar 

  80. Bichsel, S. J., Tamaskovic, R., Stegert, M. R. & Hemmings, B. A. Mechanism of activation of NDR (nuclear Dbf2-related) protein kinase by the hMOB1 protein. J. Biol. Chem. 279, 35228–35235 (2004).

    CAS  PubMed  Google Scholar 

  81. Hergovich, A., Bichsel, S. J. & Hemmings, B. A. Human NDR kinases are rapidly activated by MOB proteins through recruitment to the plasma membrane and phosphorylation. Mol. Cell. Biol. 25, 8259–8272 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Millward, T. A., Heizmann, C. W., Schafer, B. W. & Hemmings, B. A. Calcium regulation of Ndr protein kinase mediated by S100 calcium-binding proteins. EMBO J. 17, 5913–5922 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Chan, E. H. et al. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 24, 2076–2086 (2005).

    CAS  PubMed  Google Scholar 

  84. Stegert, M. R., Hergovich, A., Tamaskovic, R., Bichsel, S. J. & Hemmings, B. A. Regulation of NDR protein kinase by hydrophobic motif phosphorylation mediated by the mammalian Ste20-like kinase MST3. Mol. Cell. Biol. 25, 11019–11029 (2005). Shows that MST3 specifically phosphorylates the hydrophobic motif and not the activation-segment of NDR.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Avruch, J. et al. Rassf family of tumor suppressor polypeptides. J Biol Chem 284, 11001–11005 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Amano, M., Fukata, Y. & Kaibuchi, K. Regulation and functions of Rho-associated kinase. Exp. Cell Res. 261, 44–51 (2000).

    CAS  PubMed  Google Scholar 

  87. Di Cunto, F. et al. Citron rho-interacting kinase, a novel tissue-specific ser/thr kinase encompassing the Rho-Rac-binding protein Citron. J. Biol. Chem. 273, 29706–29711 (1998).

    CAS  PubMed  Google Scholar 

  88. Kaliman, P. & Llagostera, E. Myotonic dystrophy protein kinase (DMPK) and its role in the pathogenesis of myotonic dystrophy 1. Cell Signal. 20, 1935–1941 (2008).

    CAS  PubMed  Google Scholar 

  89. Feng, J. et al. Inhibitory phosphorylation site for Rho-associated kinase on smooth muscle myosin phosphatase. J. Biol. Chem. 274, 37385–37390 (1999).

    CAS  PubMed  Google Scholar 

  90. Zhao, Z. S. & Manser, E. PAK and other Rho-associated kinases — effectors with surprisingly diverse mechanisms of regulation. Biochem. J. 386, 201–214 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Amano, M. et al. The COOH terminus of Rho-kinase negatively regulates rho-kinase activity. J. Biol. Chem. 274, 32418–32424 (1999).

    CAS  PubMed  Google Scholar 

  92. Shimizu, M., Wang, W., Walch, E. T., Dunne, P. W. & Epstein, H. F. Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase. FEBS Lett. 475, 273–277 (2000).

    CAS  PubMed  Google Scholar 

  93. Sebbagh, M. et al. Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nature Cell Biol. 3, 346–352 (2001).

    CAS  PubMed  Google Scholar 

  94. Feng, J. et al. Rho-associated kinase of chicken gizzard smooth muscle. J. Biol. Chem, 274, 3744–3752 (1999).

    CAS  PubMed  Google Scholar 

  95. Couzens, A. L., Saridakis, V. & Scheid, M. P. The hydrophobic motif of ROCK2 requires association with the N-terminal extension for kinase activity. Biochem. J. 419, 141–148 (2009).

    CAS  PubMed  Google Scholar 

  96. Pinner, S. & Sahai, E. PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE. Nature Cell Biol. 10, 127–137 (2008).

    CAS  PubMed  Google Scholar 

  97. Valiente, M. et al. Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases. J. Biol. Chem. 280, 28936–28943 (2005).

    CAS  PubMed  Google Scholar 

  98. Boudeau, J., Miranda-Saavedra, D., Barton, G. J. & Alessi, D. R. Emerging roles of pseudokinases. Trends Cell Biol. 16, 443–452 (2006).

    CAS  PubMed  Google Scholar 

  99. Hayashi, S. et al. Identification and characterization of RPK118, a novel sphingosine kinase-1-binding protein. J. Biol. Chem. 277, 33319–33324 (2002).

    CAS  PubMed  Google Scholar 

  100. Liu, L. et al. RPK118, a PX domain-containing protein, interacts with peroxiredoxin-3 through pseudo-kinase domains. Mol. Cells 19, 39–45 (2005).

    PubMed  Google Scholar 

  101. Kennelly, P. J. & Krebs, E. G. Consensus sequences as substrate specificity determinants for protein kinases and protein phosphatases. J. Biol. Chem. 266, 15555–15558 (1991).

    CAS  PubMed  Google Scholar 

  102. Alessi, D. R., Caudwell, F. B., Andjelkovic, M., Hemmings, B. A. & Cohen, P. Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett. 399, 333–338 (1996).

    CAS  PubMed  Google Scholar 

  103. Frame, S. & Cohen, P. GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 359, 1–16 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang, H. H., Lipovsky, A. I., Dibble, C. C., Sahin, M. & Manning, B. D. S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt. Mol. Cell 24, 185–197 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Roux, P. P. et al. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J. Biol. Chem. 282, 14056–14064 (2007).

    CAS  PubMed  Google Scholar 

  106. Brunet, A. et al. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol. Cell. Biol. 21, 952–965 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Mora, A., Komander, D., Van Aalten, D. M. & Alessi, D. R. PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell. Dev. Biol. 15, 161–170 (2004).

    CAS  PubMed  Google Scholar 

  108. Murray, J. T. et al. Exploitation of KESTREL to identify N-myc downstream-regulated gene family members as physiological substrates for SGK1 and GSK3. Biochem. J. 384, 477–488 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Carpten, J. D. et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448, 439–444 (2007).

    CAS  PubMed  Google Scholar 

  110. Maurer, M. et al. 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res. 69, 6299–6306 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Meek, D. W. & Knippschild, U. Posttranslational modification of MDM2. Mol. Cancer Res. 1, 1017–1026 (2003).

    CAS  PubMed  Google Scholar 

  113. Lin, H. K. et al. Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nature Cell Biol. 11, 420–432 (2009).

    CAS  PubMed  Google Scholar 

  114. Deberardinis, R. J., Sayed, N., Ditsworth, D. & Thompson, C. B. Brick by brick: metabolism and tumor cell growth. Curr. Opin. Genet. Dev. 18, 54–61 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Wang, X. et al. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J. 20, 4370–4379 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Raught, B. et al. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 23, 1761–1769 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Carriere, A. et al. Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr. Biol. 18, 1269–1277 (2008).

    CAS  PubMed  Google Scholar 

  118. Roux, P. P., Ballif, B. A., Anjum, R., Gygi, S. P. & Blenis, J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl Acad. Sci. USA 101, 13489–13494 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Pende, M. et al. S6K1−/−/S6K2−/− mice exhibit perinatal lethality and rapamycin-sensitive 5´-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol. Cell. Biol. 24, 3112–3124 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Shahbazian, D. et al. The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO J. 25, 2781–2791 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhu, J., Blenis, J. & Yuan, J. Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc. Natl Acad. Sci. USA 105, 6584–6589 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Jones, K. T., Greer, E. R., Pearce, D. & Ashrafi, K. Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS Biol. 7, e60 (2009).

    PubMed  Google Scholar 

  123. Soukas, A. A., Kane, E. A., Carr, C. E., Melo, J. A. & Ruvkun, G. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 23, 496–511 (2009). This study, together with reference 122, suggests that SGK1 rather than Akt may be the main regulator of growth and proliferation downstream of mTORC2.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Vasudevan, K. M. et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16, 21–32 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Liu, P., Cheng, H., Roberts, T. M. & Zhao, J. J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nature Rev. Drug Discov. 8, 627–644 (2009). Excellent review describing recent progress in the development of PI3K pathway inhibitors, including those targeting AGC kinases, which also lists those being tested in clinical trials.

    CAS  Google Scholar 

  126. Peifer, C. & Alessi, D. R. Small-molecule inhibitors of PDK1. ChemMedChem 3, 1810–1838 (2008).

    CAS  PubMed  Google Scholar 

  127. Okuzumi, T. et al. Inhibitor hijacking of Akt activation. Nature Chem. Biol. 5, 484–493 (2009).

    CAS  Google Scholar 

  128. Sano, H. et al. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J. Biol. Chem. 278, 14599–14602 (2003). Describes the discovery of AS160, the sought-after regulator of insulin-stimulated GLUT4 translocation.

    CAS  PubMed  Google Scholar 

  129. Sakamoto, K. & Holman, G. D. Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. Am. J. Physiol. Endocrinol. Metab. 295, E29–E37 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. McManus, E. J. et al. Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J. 24, 1571–1583 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Li, X., Monks, B., Ge, Q. & Birnbaum, M. J. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator. Nature 447, 1012–1016 (2007).

    CAS  PubMed  Google Scholar 

  132. Puigserver, P. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1α interaction. Nature 423, 550–555 (2003).

    CAS  PubMed  Google Scholar 

  133. Cho, H. et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science 292, 1728–1731 (2001).

    CAS  PubMed  Google Scholar 

  134. Dummler, B. et al. Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Mol. Cell. Biol. 26, 8042–8051 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. White, M. F. Regulating insulin signaling and β-cell function through IRS proteins. Can. J. Physiol. Pharmacol. 84, 725–737 (2006).

    CAS  PubMed  Google Scholar 

  136. Um, S. H. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200–205 (2004).

    CAS  PubMed  Google Scholar 

  137. Tilg, H. & Moschen, A. R. Inflammatory mechanisms in the regulation of insulin resistance. Mol. Med. 14, 222–231 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Yu, C. et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 277, 50230–50236 (2002).

    CAS  PubMed  Google Scholar 

  139. Kim, J. K. et al. PKC-θ knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 114, 823–827 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Engel, M. et al. Allosteric activation of the protein kinase PDK1 with low molecular weight compounds. EMBO J. 25, 5469–5480 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Hindie, V. et al. Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1. Nature Chem. Biol. 5, 758–764 (2009).

    CAS  Google Scholar 

  142. Yamamoto, S., Sippel, K. C., Berson, E. L. & Dryja, T. P. Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness. Nature Genet. 15, 175–178 (1997).

    CAS  PubMed  Google Scholar 

  143. Cideciyan, A. V. et al. Null mutation in the rhodopsin kinase gene slows recovery kinetics of rod and cone phototransduction in man. Proc. Natl Acad. Sci. USA 95, 328–333 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Stevanin, G. et al. Mutation in the catalytic domain of protein kinase C γ and extension of the phenotype associated with spinocerebellar ataxia type 14. Arch. Neurol. 61, 1242–1248 (2004).

    PubMed  Google Scholar 

  145. Yabe, I. et al. Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C γ. Arch. Neurol. 60, 1749–1751 (2003).

    PubMed  Google Scholar 

  146. Trivier, E. et al. Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 384, 567–570 (1996).

    CAS  PubMed  Google Scholar 

  147. Schiebel, K. et al. Abnormal XY interchange between a novel isolated protein kinase gene, PRKY, and its homologue, PRKX, accounts for one third of all (Y+)XX males and (Y−)XY females. Hum. Mol. Genet. 6, 1985–1989 (1997).

    CAS  PubMed  Google Scholar 

  148. Machuca-Tzili, L., Brook, D. & Hilton-Jones, D. Clinical and molecular aspects of the myotonic dystrophies: a review. Muscle Nerve 32, 1–18 (2005).

    CAS  PubMed  Google Scholar 

  149. Cho, D. H. & Tapscott, S. J. Myotonic dystrophy: emerging mechanisms for DM1 and DM2. Biochim. Biophys. Acta 1772, 195–204 (2007).

    CAS  PubMed  Google Scholar 

  150. Labbe, C. et al. MAST3: a novel IBD risk factor that modulates TLR4 signaling. Genes Immun. 9, 602–612 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Gandhi, M. J., Cummings, C. L. & Drachman, J. G. FLJ14813 missense mutation: a candidate for autosomal dominant thrombocytopenia on human chromosome 10. Hum. Hered. 55, 66–70 (2003).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Medical Research Council (L.R.P., D.K., D.R.A.) and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer–Ingelheim, GlaxoSmithKline, Merck KgaA and Pfizer) for financial support.

Author information

Authors and Affiliations

  1. MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK

    Laura R. Pearce & Dario R. Alessi

  2. Division of Protein and Nucleic Acid Chemistry, Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK

    David Komander

Authors
  1. Laura R. Pearce
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. David Komander
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Dario R. Alessi
    View author publications

    You can also search for this author inPubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Related links

Related links

DATABASES

Protein data bank

AKT2 

PKCβ2

ROCK1

FURTHER INFORMATION

Dario R. Alessi's homepage

Glossary

Hydrophobic motif

A motif found in most AGC kinases, which is located at the carboxyl terminus of the catalytic domain. It consists of a phosphorylatable Ser or Thr residue flanked by hydrophobic residues, and its phosphorylation is required for stabilization and activation of the kinase.

Turn motif

A motif found in some AGC kinases, which is located at the carboxyl terminus of the catalytic domain. It consists of a phosphorylatable Ser or Thr residue followed by a Pro residue. Its phosphorylation is required for kinase stability and may also protect the hydrophobic motif site from dephosphorylation.

Pleckstrin homology (PH) domain

A sequence of approximately100 amino acids that is present in many signalling molecules and binds to phosphatidylinositol lipids, facilitating membrane interactions.

Agonist

A molecule that binds to and stimulates a receptor to trigger a response by the cell.

Second messenger

An intracellular signalling molecule, such as cyclic AMP, diacylglycerol or inositol triphosphate, that is rapidly and transiently synthesized following receptor activation to further amplify the signal transduction cascade.

PDK1-interacting fragment (PIF) pocket

A docking site found in the kinase domain of 3-phosphoinositide-dependent protein kinase 1. It consists of basic residues, which bind the phosphorylated hydrophobic motif of a substrate, for example p70 ribosomal S6 kinase 1.

Phox homology (PX) domain

A lipid- and protein-interaction domain that consists of 100–130 amino acids and is defined by sequences that are found in two components of the phagocyte NADPH oxidase (phox) complex.

Pseudosubstrate

A short sequence similar to that of a substrate except it lacks a phosphorylatable residue. Binding to the kinase catalytic domain prevents substrate binding and maintains the kinase in an inactive state.

Heptapeptide repeat 1 domain

An α-helical domain that forms an antiparallel coiled coil fold known as an ACC finger. It enables binding to the small G protein rho.

Coiled-coil motif

A protein structural domain that mediates subunit oligomerization. Coiled coils contain between two and five helices that twist around each other to form a supercoil.

Long-term potentiation

A long-lasting increase in the size of the postsynaptic response to synaptic transmissions, which is thought to be a key mechanism for learning and long-term memory formation in the brain.

Heterotrimeric G protein

A protein that consists of an α-subunit, which binds GTP, and β- and γ-subunits. The α-subunit is GDP bound until stimulation of GPCR signalling, when GDP is exchanged for GTP. The α-subunit subsequently dissociates from the βγ subunits, leading to the initiation of signalling through α- and βγ binding to effectors such as adenylate cyclase and phospholipase.

Farnesylation

A post-translational modification in which a farnesyl group (a hydrophobic group of three isoprene units) is conjugated to proteins, such as Ras GTPases, that contain a carboxy-terminal CAAX motif. Farnesylation promotes attachment of the modified proteins to membranes.

Palmitoylation

A post-translational modification of a protein by the covalent attachment of a palmitate (a 16-carbon saturated fatty acid) to a cysteine residue through a thioester bond. Palmitoylation promotes attachment of the modified proteins to membranes.

EF hand

A structural domain composed of two helices (E and F) that are linked by a short loop region which binds calcium.

Pseudokinase

A protein that contains a kinase-like domain but lacks at least one of the conserved residues required for catalytic activity, and therefore is predicted to be inactive. Fourty-eight pseudokinases seem to be encoded in the human genome.

DFG

A motif (Asp–Phe–Gly) that is found in subdomain VII of the kinase catalytic domain. The aspartic acid binds Mg2+ ions, which in turn coordinate the β- and γ-phosphates of ATP in the ATP-binding site. The position of the DFG motif determines kinase activity.

VAIK

A motif (Val–Ala–Ile–Lys) that is found in subdomain II of the kinase catalytic domain. The Lys residue is involved in orienting ATP by interacting with the α- and β-phosphates of ATP.

14-3-3 protein

An adaptor protein that binds to phosphorylated Ser and Thr residues, causing changes in the target protein's enzymatic activity and subcellular localization.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pearce, L., Komander, D. & Alessi, D. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 11, 9–22 (2010). https://doi.org/10.1038/nrm2822

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2822

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing