| 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] [RASF5_HUMAN] Potential tumor suppressor. Seems to be involved in lymphocyte adhesion by linking RAP1A activation upon T-cell receptor or chemokine stimulation to integrin activation. Isoform 2 stimulates lymphocyte polarization and the patch-like distribution of ITGAL/LFA-1, resulting in an enhanced adhesion to ICAM1. Together with RAP1A may participate in regulation of microtubule growth. The association of isoform 2 with activated RAP1A is required for directional movement of endothelial cells during wound healing. May be involved in regulation of Ras apoptotic function. The RASSF5-STK4/MST1 complex may mediate HRAS1 and KRAS induced apoptosis.[17] [18] [19]
Publication Abstract from PubMed
Despite recent progress in research on the Hippo signalling pathway, the structural information available in this area is extremely limited. Intriguingly, the homodimeric and heterodimeric interactions of mammalian sterile 20-like (MST) kinases through the so-called `SARAH' (SAV/RASSF/HPO) domains play a critical role in cellular homeostasis, dictating the fate of the cell regarding cell proliferation or apoptosis. To understand the mechanism of the heterodimerization of SARAH domains, the three-dimensional structures of an MST1-RASSF5 SARAH heterodimer and an MST2 SARAH homodimer were determined by X-ray crystallography and were analysed together with that previously determined for the MST1 SARAH homodimer. While the structure of the MST2 homodimer resembled that of the MST1 homodimer, the MST1-RASSF5 heterodimer showed distinct structural features. Firstly, the six N-terminal residues (Asp432-Lys437), which correspond to the short N-terminal 310-helix h1 kinked from the h2 helix in the MST1 homodimer, were disordered. Furthermore, the MST1 SARAH domain in the MST1-RASSF5 complex showed a longer helical structure (Ser438-Lys480) than that in the MST1 homodimer (Val441-Lys480). Moreover, extensive polar and nonpolar contacts in the MST1-RASSF5 SARAH domain were identified which strengthen the interactions in the heterodimer in comparison to the interactions in the homodimer. Denaturation experiments performed using urea also indicated that the MST-RASSF heterodimers are substantially more stable than the MST homodimers. These findings provide structural insights into the role of the MST1-RASSF5 SARAH domain in apoptosis signalling.
Structural basis of the heterodimerization of the MST and RASSF SARAH domains in the Hippo signalling pathway.,Hwang E, Cheong HK, Mushtaq AU, Kim HY, Yeo KJ, Kim E, Lee WC, Hwang KY, Cheong C, Jeon YH Acta Crystallogr D Biol Crystallogr. 2014 Jul 1;70(Pt 7):1944-53. doi:, 10.1107/S139900471400947X. Epub 2014 Jun 29. PMID:25004971[20]
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
- ↑ Katagiri K, Maeda A, Shimonaka M, Kinashi T. RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nat Immunol. 2003 Aug;4(8):741-8. Epub 2003 Jul 6. PMID:12845325 doi:10.1038/ni950
- ↑ Vos MD, Martinez A, Ellis CA, Vallecorsa T, Clark GJ. The pro-apoptotic Ras effector Nore1 may serve as a Ras-regulated tumor suppressor in the lung. J Biol Chem. 2003 Jun 13;278(24):21938-43. Epub 2003 Apr 3. PMID:12676952 doi:10.1074/jbc.M211019200
- ↑ Fujita H, Fukuhara S, Sakurai A, Yamagishi A, Kamioka Y, Nakaoka Y, Masuda M, Mochizuki N. Local activation of Rap1 contributes to directional vascular endothelial cell migration accompanied by extension of microtubules on which RAPL, a Rap1-associating molecule, localizes. J Biol Chem. 2005 Feb 11;280(6):5022-31. Epub 2004 Nov 29. PMID:15569673 doi:10.1074/jbc.M409701200
- ↑ Hwang E, Cheong HK, Mushtaq AU, Kim HY, Yeo KJ, Kim E, Lee WC, Hwang KY, Cheong C, Jeon YH. Structural basis of the heterodimerization of the MST and RASSF SARAH domains in the Hippo signalling pathway. Acta Crystallogr D Biol Crystallogr. 2014 Jul 1;70(Pt 7):1944-53. doi:, 10.1107/S139900471400947X. Epub 2014 Jun 29. PMID:25004971 doi:http://dx.doi.org/10.1107/S139900471400947X
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