| Structural highlights
Function
KS6A1_HUMAN Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1, which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
Mitogen-activated protein kinases (MAPKs) bind and activate their downstream kinase substrates, MAPK-activated protein kinases (MAPKAPKs). Notably, extracellular signal regulated kinase 2 (ERK2) phosphorylates ribosomal S6 kinase 1 (RSK1), which promotes cellular growth. Here, we determined the crystal structure of an RSK1 construct in complex with its activator kinase. The structure captures the kinase-kinase complex in a precatalytic state where the activation loop of the downstream kinase (RSK1) faces the enzyme's (ERK2) catalytic site. Molecular dynamics simulation was used to show how this heterodimer could shift into a signaling-competent state. This structural analysis combined with biochemical and cellular studies on MAPK-->MAPKAPK signaling showed that the interaction between the MAPK binding linear motif (residing in a disordered kinase domain extension) and the ERK2 "docking" groove plays the major role in making an encounter complex. This interaction holds kinase domains proximal as they "readjust," whereas generic kinase domain surface contacts bring them into a catalytically competent state.
Structural assembly of the signaling competent ERK2-RSK1 heterodimeric protein kinase complex.,Alexa A, Gogl G, Glatz G, Garai A, Zeke A, Varga J, Dudas E, Jeszenoi N, Bodor A, Hetenyi C, Remenyi A Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2711-6. doi: 10.1073/pnas.1417571112., Epub 2015 Feb 17. PMID:25730857[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dalby KN, Morrice N, Caudwell FB, 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. 1998 Jan 16;273(3):1496-505. PMID:9430688
- ↑ Shimamura A, Ballif BA, Richards SA, Blenis J. Rsk1 mediates a MEK-MAP kinase cell survival signal. Curr Biol. 2000 Feb 10;10(3):127-35. PMID:10679322
- ↑ Buck M, Poli V, Hunter T, Chojkier M. C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival. Mol Cell. 2001 Oct;8(4):807-16. PMID:11684016
- ↑ Wu J, Janknecht R. Regulation of the ETS transcription factor ER81 by the 90-kDa ribosomal S6 kinase 1 and protein kinase A. J Biol Chem. 2002 Nov 8;277(45):42669-79. Epub 2002 Sep 3. PMID:12213813 doi:10.1074/jbc.M205501200
- ↑ Hu Y, Fang X, Dunham SM, Prada C, Stachowiak EK, Stachowiak MK. 90-kDa ribosomal S6 kinase is a direct target for the nuclear fibroblast growth factor receptor 1 (FGFR1): role in FGFR1 signaling. J Biol Chem. 2004 Jul 9;279(28):29325-35. Epub 2004 Apr 26. PMID:15117958 doi:10.1074/jbc.M311144200
- ↑ Roux PP, Ballif BA, Anjum R, Gygi SP, 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 U S A. 2004 Sep 14;101(37):13489-94. Epub 2004 Sep 1. PMID:15342917 doi:10.1073/pnas.0405659101
- ↑ Anjum R, Roux PP, Ballif BA, Gygi SP, Blenis J. The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling. Curr Biol. 2005 Oct 11;15(19):1762-7. PMID:16213824 doi:10.1016/j.cub.2005.08.050
- ↑ Wingate AD, Campbell DG, Peggie M, Arthur JS. Nur77 is phosphorylated in cells by RSK in response to mitogenic stimulation. Biochem J. 2006 Feb 1;393(Pt 3):715-24. PMID:16223362 doi:10.1042/BJ20050967
- ↑ Shahbazian D, Roux PP, Mieulet V, Cohen MS, Raught B, Taunton J, Hershey JW, Blenis J, Pende M, Sonenberg N. The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO J. 2006 Jun 21;25(12):2781-91. Epub 2006 Jun 8. PMID:16763566 doi:10.1038/sj.emboj.7601166
- ↑ Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem. 2007 May 11;282(19):14056-64. Epub 2007 Mar 14. PMID:17360704 doi:10.1074/jbc.M700906200
- ↑ Carriere A, Cargnello M, Julien LA, Gao H, Bonneil E, Thibault P, Roux PP. Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr Biol. 2008 Sep 9;18(17):1269-77. doi: 10.1016/j.cub.2008.07.078. Epub 2008, Aug 21. PMID:18722121 doi:10.1016/j.cub.2008.07.078
- ↑ Alexa A, Gogl G, Glatz G, Garai A, Zeke A, Varga J, Dudas E, Jeszenoi N, Bodor A, Hetenyi C, Remenyi A. Structural assembly of the signaling competent ERK2-RSK1 heterodimeric protein kinase complex. Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2711-6. doi: 10.1073/pnas.1417571112., Epub 2015 Feb 17. PMID:25730857 doi:http://dx.doi.org/10.1073/pnas.1417571112
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