| Structural highlights
Function
[PKN1_HUMAN] PKC-related serine/threonine-protein kinase involved in various processes such as regulation of the intermediate filaments of the actin cytoskeleton, cell migration, tumor cell invasion and transcription regulation. Regulates the cytoskeletal network by phosphorylating proteins such as VIM and neurofilament proteins NEFH, NEFL and NEFM, leading to inhibit their polymerization. Phosphorylates 'Ser-575', 'Ser-637' and 'Ser-669' of MAPT/Tau, lowering its ability to bind to microtubules, resulting in disruption of tubulin assembly. Acts as a key coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-11' of histone H3 (H3T11ph), a specific tag for epigenetic transcriptional activation that promotes demethylation of histone H3 'Lys-9' (H3K9me) by KDM4C/JMJD2C. Phosphorylates HDAC5, HDAC7 and HDAC9, leading to impair their import in the nucleus. Phosphorylates 'Thr-38' of PPP1R14A, 'Ser-159', 'Ser-163' and 'Ser-170' of MARCKS, and GFAP. Able to phosphorylate RPS6 in vitro.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
Protein kinase C related kinase 1 (PRK1) is a component of Rho-GTPase, androgen receptor, histone demethylase and histone deacetylase signaling pathways implicated in prostate and ovarian cancer. Herein we describe the crystal structure of PRK1 in apo form, and also in complex with a panel of literature inhibitors including the clinical candidates lestaurtinib and tofacitinib, as well as the staurosporine analog Ro-31-8220. PRK1 is a member of the AGC-kinase class, and as such exhibits the characteristic regulatory sequence at the C-terminus of the catalytic domain - the 'C-tail'. The C-tail fully encircles the catalytic domain placing a phenylalanine in the ATP-binding site. Our inhibitor structures include examples of molecules which both interact with, and displace the C-tail from the active site. This information may assist in the design of inhibitors targeting both PRK and other members of the AGC kinase family.
Crystal Structures of PRK1 in Complex with the Clinical Compounds Lestaurtinib and Tofacitinib Reveal Ligand Induced Conformational Changes.,Chamberlain P, Delker S, Pagarigan B, Mahmoudi A, Jackson P, Abbasian M, Muir J, Raheja N, Cathers B PLoS One. 2014 Aug 11;9(8):e103638. doi: 10.1371/journal.pone.0103638., eCollection 2014. PMID:25111382[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Palmer RH, Schonwasser DC, Rahman D, Pappin DJ, Herget T, Parker PJ. PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. FEBS Lett. 1996 Jan 15;378(3):281-5. PMID:8557118
- ↑ Mukai H, Toshimori M, Shibata H, Kitagawa M, Shimakawa M, Miyahara M, Sunakawa H, Ono Y. PKN associates and phosphorylates the head-rod domain of neurofilament protein. J Biol Chem. 1996 Apr 19;271(16):9816-22. PMID:8621664
- ↑ Matsuzawa K, Kosako H, Inagaki N, Shibata H, Mukai H, Ono Y, Amano M, Kaibuchi K, Matsuura Y, Azuma I, Inagaki M. Domain-specific phosphorylation of vimentin and glial fibrillary acidic protein by PKN. Biochem Biophys Res Commun. 1997 May 29;234(3):621-5. PMID:9175763 doi:https://dx.doi.org/10.1006/bbrc.1997.6669
- ↑ Taniguchi T, Kawamata T, Mukai H, Hasegawa H, Isagawa T, Yasuda M, Hashimoto T, Terashima A, Nakai M, Mori H, Ono Y, Tanaka C. Phosphorylation of tau is regulated by PKN. J Biol Chem. 2001 Mar 30;276(13):10025-31. Epub 2000 Dec 4. PMID:11104762 doi:https://dx.doi.org/10.1074/jbc.M007427200
- ↑ Metzger E, Muller JM, Ferrari S, Buettner R, Schule R. A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer. EMBO J. 2003 Jan 15;22(2):270-80. PMID:12514133 doi:https://dx.doi.org/10.1093/emboj/cdg023
- ↑ Schmidt A, Durgan J, Magalhaes A, Hall A. Rho GTPases regulate PRK2/PKN2 to control entry into mitosis and exit from cytokinesis. EMBO J. 2007 Mar 21;26(6):1624-36. Epub 2007 Mar 1. PMID:17332740 doi:https://dx.doi.org/10.1038/sj.emboj.7601637
- ↑ Metzger E, Yin N, Wissmann M, Kunowska N, Fischer K, Friedrichs N, Patnaik D, Higgins JM, Potier N, Scheidtmann KH, Buettner R, Schule R. Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation. Nat Cell Biol. 2008 Jan;10(1):53-60. Epub 2007 Dec 9. PMID:18066052 doi:https://dx.doi.org/10.1038/ncb1668
- ↑ Harrison BC, Huynh K, Lundgaard GL, Helmke SM, Perryman MB, McKinsey TA. Protein kinase C-related kinase targets nuclear localization signals in a subset of class IIa histone deacetylases. FEBS Lett. 2010 Mar 19;584(6):1103-10. doi: 10.1016/j.febslet.2010.02.057. Epub, 2010 Feb 24. PMID:20188095 doi:https://dx.doi.org/10.1016/j.febslet.2010.02.057
- ↑ Lachmann S, Jevons A, De Rycker M, Casamassima A, Radtke S, Collazos A, Parker PJ. Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration. PLoS One. 2011;6(7):e21732. doi: 10.1371/journal.pone.0021732. Epub 2011 Jul 6. PMID:21754995 doi:https://dx.doi.org/10.1371/journal.pone.0021732
- ↑ Chamberlain P, Delker S, Pagarigan B, Mahmoudi A, Jackson P, Abbasian M, Muir J, Raheja N, Cathers B. Crystal Structures of PRK1 in Complex with the Clinical Compounds Lestaurtinib and Tofacitinib Reveal Ligand Induced Conformational Changes. PLoS One. 2014 Aug 11;9(8):e103638. doi: 10.1371/journal.pone.0103638., eCollection 2014. PMID:25111382 doi:https://dx.doi.org/10.1371/journal.pone.0103638
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