| Structural highlights
Function
STK4_HUMAN Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation (By similarity). Phosphorylates 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation. Phosphorylates MOBKL1A, MOBKL1B and RASSF2. Phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylates FOXO1 on 'Ser-212' and regulates its activation and stimulates transcription of PMAIP1 in a FOXO1-dependent manner. Phosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53 deacetylation, thereby promoting p53/TP53 dependent transcription and apoptosis upon DNA damage. Acts as an inhibitor of PKB/AKT1. Phosphorylates AR on 'Ser-650' and suppresses its activity by intersecting with PKB/AKT1 signaling and antagonizing formation of AR-chromatin complexes.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
In eukaryotic cells, apoptosis and cell cycle arrest by the Ras --> RASSF --> MST pathway are controlled by the interaction of SARAH (for Salvador/Rassf/Hippo) domains in the C-terminal part of tumor suppressor proteins. The Mst1 SARAH domain interacts with its homologous domain of Rassf1 and Rassf5 (also known as Nore1) by forming a heterodimer that mediates the apoptosis process. Here, we describe the homodimeric structure of the human Mst1 SARAH domain and its heterotypic interaction with the Rassf5 and Salvador (Sav) SARAH domain. The Mst1 SARAH structure forms a homodimer containing two helices per monomer. An antiparallel arrangement of the long alpha-helices (h2/h2') provides an elongated binding interface between the two monomers, and the short 3(10) helices (h1/h1') are folded toward that of the other monomer. Chemical shift perturbation experiments identified an elongated, tight-binding interface with the Rassf5 SARAH domain and a 1:1 heterodimer formation. The linker region between the kinase and the SARAH domain is shown to be disordered in the free protein. These results imply a novel mode of interaction with RASSF family proteins and provide insight into the mechanism of apoptosis control by the SARAH domain.
Structural insight into dimeric interaction of the SARAH domains from Mst1 and RASSF family proteins in the apoptosis pathway.,Hwang E, Ryu KS, Paakkonen K, Guntert P, Cheong HK, Lim DS, Lee JO, Jeon YH, Cheong C Proc Natl Acad Sci U S A. 2007 May 29;104(22):9236-41. Epub 2007 May 21. PMID:17517604[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Taylor LK, Wang HC, Erikson RL. Newly identified stress-responsive protein kinases, Krs-1 and Krs-2. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10099-104. PMID:8816758
- ↑ Creasy CL, Ambrose DM, Chernoff J. The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain. J Biol Chem. 1996 Aug 30;271(35):21049-53. PMID:8702870
- ↑ Lee KK, Ohyama T, Yajima N, Tsubuki S, Yonehara S. MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation. J Biol Chem. 2001 Jun 1;276(22):19276-85. Epub 2001 Mar 7. PMID:11278283 doi:http://dx.doi.org/10.1074/jbc.M005109200
- ↑ Ura S, Masuyama N, Graves JD, Gotoh Y. Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation. Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10148-53. Epub 2001 Aug 21. PMID:11517310 doi:http://dx.doi.org/10.1073/pnas.181161698
- ↑ Cheung WL, Ajiro K, Samejima K, Kloc M, Cheung P, Mizzen CA, Beeser A, Etkin LD, Chernoff J, Earnshaw WC, Allis CD. Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell. 2003 May 16;113(4):507-17. PMID:12757711
- ↑ Praskova M, Khoklatchev A, Ortiz-Vega S, Avruch J. Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras. Biochem J. 2004 Jul 15;381(Pt 2):453-62. PMID:15109305 doi:http://dx.doi.org/10.1042/BJ20040025
- ↑ Oh HJ, Lee KK, Song SJ, Jin MS, Song MS, Lee JH, Im CR, Lee JO, Yonehara S, Lim DS. Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis. Cancer Res. 2006 Mar 1;66(5):2562-9. PMID:16510573 doi:http://dx.doi.org/66/5/2562
- ↑ Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villen J, Becker EB, DiBacco S, de la Iglesia N, Gygi S, Blackwell TK, Bonni A. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell. 2006 Jun 2;125(5):987-1001. PMID:16751106 doi:S0092-8674(06)00559-9
- ↑ Callus BA, Verhagen AM, Vaux DL. Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. FEBS J. 2006 Sep;273(18):4264-76. Epub 2006 Aug 23. PMID:16930133 doi:EJB5427
- ↑ Cinar B, Fang PK, Lutchman M, Di Vizio D, Adam RM, Pavlova N, Rubin MA, Yelick PC, Freeman MR. The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1. EMBO J. 2007 Oct 31;26(21):4523-34. Epub 2007 Oct 11. PMID:17932490 doi:http://dx.doi.org/10.1038/sj.emboj.7601872
- ↑ Praskova M, Xia F, Avruch J. MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr Biol. 2008 Mar 11;18(5):311-21. doi: 10.1016/j.cub.2008.02.006. PMID:18328708 doi:10.1016/j.cub.2008.02.006
- ↑ You B, Yan G, Zhang Z, Yan L, Li J, Ge Q, Jin JP, Sun J. Phosphorylation of cardiac troponin I by mammalian sterile 20-like kinase 1. Biochem J. 2009 Feb 15;418(1):93-101. doi: 10.1042/BJ20081340. PMID:18986304 doi:http://dx.doi.org/10.1042/BJ20081340
- ↑ Cooper WN, Hesson LB, Matallanas D, Dallol A, von Kriegsheim A, Ward R, Kolch W, Latif F. RASSF2 associates with and stabilizes the proapoptotic kinase MST2. Oncogene. 2009 Aug 20;28(33):2988-98. doi: 10.1038/onc.2009.152. Epub 2009 Jun, 15. PMID:19525978 doi:10.1038/onc.2009.152
- ↑ Valis K, Prochazka L, Boura E, Chladova J, Obsil T, Rohlena J, Truksa J, Dong LF, Ralph SJ, Neuzil J. Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner. Cancer Res. 2011 Feb 1;71(3):946-54. doi: 10.1158/0008-5472.CAN-10-2203. Epub, 2011 Jan 18. PMID:21245099 doi:10.1158/0008-5472.CAN-10-2203
- ↑ Cinar B, Collak FK, Lopez D, Akgul S, Mukhopadhyay NK, Kilicarslan M, Gioeli DG, Freeman MR. MST1 is a multifunctional caspase-independent inhibitor of androgenic signaling. Cancer Res. 2011 Jun 15;71(12):4303-13. doi: 10.1158/0008-5472.CAN-10-4532. Epub , 2011 Apr 21. PMID:21512132 doi:http://dx.doi.org/10.1158/0008-5472.CAN-10-4532
- ↑ Yuan F, Xie Q, Wu J, Bai Y, Mao B, Dong Y, Bi W, Ji G, Tao W, Wang Y, Yuan Z. MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation. J Biol Chem. 2011 Mar 4;286(9):6940-5. doi: 10.1074/jbc.M110.182543. Epub 2011, Jan 6. PMID:21212262 doi:http://dx.doi.org/10.1074/jbc.M110.182543
- ↑ Hwang E, Ryu KS, Paakkonen K, Guntert P, Cheong HK, Lim DS, Lee JO, Jeon YH, Cheong C. Structural insight into dimeric interaction of the SARAH domains from Mst1 and RASSF family proteins in the apoptosis pathway. Proc Natl Acad Sci U S A. 2007 May 29;104(22):9236-41. Epub 2007 May 21. PMID:17517604
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