Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8361780 | Seminars in Cancer Biology | 2018 | 46 Pages |
Abstract
The group of AGC kinases consists of 63 evolutionarily related serine/threonine protein kinases comprising PDK1, PKB/Akt, SGK, PKC, PRK/PKN, MSK, RSK, S6K, PKA, PKG, DMPK, MRCK, ROCK, NDR, LATS, CRIK, MAST, GRK, Sgk494, and YANK, while two other families, Aurora and PLK, are the most closely related to the group. Eight of these families are physiologically activated downstream of growth factor signalling, while other AGC kinases are downstream effectors of a wide range of signals. The different AGC kinase families share aspects of their mechanisms of inhibition and activation. In the present review, we update the knowledge of the mechanisms of regulation of different AGC kinases. The conformation of the catalytic domain of many AGC kinases is regulated allosterically through the modulation of the conformation of a regulatory site on the small lobe of the kinase domain, the PIF-pocket. The PIF-pocket acts like an ON-OFF switch in AGC kinases with different modes of regulation, i.e. PDK1, PKB/Akt, LATS and Aurora kinases. In this review, we make emphasis on how the knowledge of the molecular mechanisms of regulation can guide the discovery and development of small allosteric modulators. Molecular probes stabilizing the PIF-pocket in the active conformation are activators, while compounds stabilizing the disrupted site are allosteric inhibitors. One challenge for the rational development of allosteric modulators is the lack of complete structural information of the inhibited forms of full-length AGC kinases. On the other hand, we suggest that the available information derived from molecular biology and biochemical studies can already guide screening strategies for the identification of innovative mode of action molecular probes and the development of selective allosteric drugs for the treatment of human diseases.
Keywords
MSKPDK1-interacting fragmentmicrotubule-associated protein kinasemyotonic dystrophy protein kinaseAGC kinaseMRCKRSKPLKS6KDMPKNDRPDK1PRKPIFpKaGRKPKCPKGPKBG protein-coupled receptor kinaseSGKAurora kinaseAllostericMolecular dynamicsAURORALatsmastRegulationHydrophobic motif3-phosphoinositide-dependent protein kinase 1protein kinase Aprotein kinase GProtein kinase Cmitogen- and stress-activated protein kinaseRho-associated protein kinaseDrug discoveryPolo-like kinaseRock
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Authors
Alejandro E. Leroux, Jörg O. Schulze, Ricardo M. Biondi,