Regulation of Proapoptotic Mammalian Ste20-like Kinase MST2 by the IGF1-Akt Pathway

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2010 Mar 17

PMID 20231902

Citations 24

Authors

Donghwa Kim

Shaokun Shu

Marc D Coppola

Satoshi Kaneko

Zeng-Qiang Yuan

Jin Q Cheng

Affiliations

Soon will be listed here.

Abstract

Background: Hippo, a Drosophila serine/threonine kinase, promotes apoptosis and restricts cell growth and proliferation. Its mammalian homolog MST2 has been shown to play similar role and be regulated by Raf-1 via a kinase-independent mechanism and by RASSF family proteins through forming complex with MST2. However, regulation of MST2 by cell survival signal remains largely unknown.

Methodology/principal Findings: Using immunoblotting, in vitro kinase and in vivo labeling assays, we show that IGF1 inhibits MST2 cleavage and activation induced by DNA damage through the phosphatidylinosotol 3-kinase (PI3K)/Akt pathway. Akt phosphorylates a highly conserved threonine-117 residue of MST2 in vitro and in vivo, which leads to inhibition of MST2 cleavage, nuclear translocation, autophosphorylation-Thr180 and kinase activity. As a result, MST2 proapoptotic and growth arrest function was significantly reduced. Further, inverse correlation between pMST2-T117/pAkt and pMST2-T180 was observed in human breast tumors.

Conclusions/significance: Our findings demonstrate for the first time that extracellular cell survival signal IGF1 regulates MST2 and that Akt is a key upstream regulator of MST2.

Citing Articles

Retraction: Regulation of Proapoptotic Mammalian ste20-Like Kinase MST2 by the IGF1-Akt Pathway.

PLoS One. 2023; 18(7):e0289329.

PMID: 37490513 PMC: 10368252. DOI: 10.1371/journal.pone.0289329.

The hippo kinases MST1/2 in cardiovascular and metabolic diseases: A promising therapeutic target option for pharmacotherapy.

Yin Y, Tan M, Han L, Zhang L, Zhang Y, Zhang J Acta Pharm Sin B. 2023; 13(5):1956-1975.

PMID: 37250161 PMC: 10213817. DOI: 10.1016/j.apsb.2023.01.015.

Evaluation of the anti-RANKL monoclonal antibody in rheumatoid arthritis rats.

Lv D, Zhao X Arch Rheumatol. 2023; 38(1):22-31.

PMID: 37235123 PMC: 10208611. DOI: 10.46497/ArchRheumatol.2023.9240.

Neonatal Cardiovascular-Progenitor-Cell-Derived Extracellular Vesicles Activate YAP1 in Adult Cardiac Progenitor Cells.

Ceja L, Escopete S, Hughes L, Lopez L, Camberos V, Vallejos P Int J Mol Sci. 2023; 24(9).

PMID: 37175796 PMC: 10179407. DOI: 10.3390/ijms24098088.

Inhibition of colorectal cancer tumorigenesis by ursolic acid and doxorubicin is mediated by targeting the Akt signaling pathway and activating the Hippo signaling pathway.

Hu D, Meng R, Nguyen T, Chai O, Park B, Lee J Mol Med Rep. 2022; 27(1).

PMID: 36382656 PMC: 9685224. DOI: 10.3892/mmr.2022.12898.

References

Zhao B, Wei X, Li W, Udan R, Yang Q, Kim J . Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007; 21(21):2747-61. PMC: 2045129. DOI: 10.1101/gad.1602907. View

Cinar B, Fang P, Lutchman M, Di Vizio D, Adam R, Pavlova N . The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1. EMBO J. 2007; 26(21):4523-34. PMC: 2063482. DOI: 10.1038/sj.emboj.7601872. View

Vichalkovski A, Gresko E, Cornils H, Hergovich A, Schmitz D, Hemmings B . NDR kinase is activated by RASSF1A/MST1 in response to Fas receptor stimulation and promotes apoptosis. Curr Biol. 2008; 18(23):1889-95. DOI: 10.1016/j.cub.2008.10.060. View

Zhou D, Medoff B, Chen L, Li L, Zhang X, Praskova M . The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naïve T cells. Proc Natl Acad Sci U S A. 2008; 105(51):20321-6. PMC: 2600581. DOI: 10.1073/pnas.0810773105. View

Ikeda M, Kawata A, Nishikawa M, Tateishi Y, Yamaguchi M, Nakagawa K . Hippo pathway-dependent and -independent roles of RASSF6. Sci Signal. 2009; 2(90):ra59. DOI: 10.1126/scisignal.2000300. View

Creasy C, Chernoff J . Cloning and characterization of a member of the MST subfamily of Ste20-like kinases. Gene. 1995; 167(1-2):303-6. DOI: 10.1016/0378-1119(95)00653-2. View

Datta S, Brunet A, Greenberg M . Cellular survival: a play in three Akts. Genes Dev. 1999; 13(22):2905-27. DOI: 10.1101/gad.13.22.2905. View

Verdu J, Buratovich M, Wilder E, Birnbaum M . Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nat Cell Biol. 1999; 1(8):500-6. DOI: 10.1038/70293. View

Kim A, Khursigara G, Sun X, Franke T, Chao M . Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol. 2001; 21(3):893-901. PMC: 86680. DOI: 10.1128/MCB.21.3.893-901.2001. View

10.

Sun M, Wang G, Paciga J, Feldman R, Yuan Z, Ma X . AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol. 2001; 159(2):431-7. PMC: 1850562. DOI: 10.1016/s0002-9440(10)61714-2. View

11.

Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang X . Identification of a novel Ras-regulated proapoptotic pathway. Curr Biol. 2002; 12(4):253-65. DOI: 10.1016/s0960-9822(02)00683-8. View

12.

Cheung W, Ajiro K, Samejima K, Kloc M, Cheung P, Mizzen C . Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell. 2003; 113(4):507-17. DOI: 10.1016/s0092-8674(03)00355-6. View

13.

Wu S, Huang J, Dong J, Pan D . hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell. 2003; 114(4):445-56. DOI: 10.1016/s0092-8674(03)00549-x. View

14.

Harvey K, Pfleger C, Hariharan I . The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell. 2003; 114(4):457-67. DOI: 10.1016/s0092-8674(03)00557-9. View

15.

Udan R, Kango-Singh M, Nolo R, Tao C, Halder G . Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol. 2003; 5(10):914-20. DOI: 10.1038/ncb1050. View

16.

Miron M, Lasko P, Sonenberg N . Signaling from Akt to FRAP/TOR targets both 4E-BP and S6K in Drosophila melanogaster. Mol Cell Biol. 2003; 23(24):9117-26. PMC: 309682. DOI: 10.1128/MCB.23.24.9117-9126.2003. View

17.

Dan H, Sun M, Kaneko S, Feldman R, Nicosia S, Wang H . Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem. 2003; 279(7):5405-12. DOI: 10.1074/jbc.M312044200. View

18.

Gardai S, Hildeman D, Frankel S, Whitlock B, Frasch S, Borregaard N . Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem. 2004; 279(20):21085-95. DOI: 10.1074/jbc.M400063200. View

19.

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; 381(Pt 2):453-62. PMC: 1133852. DOI: 10.1042/BJ20040025. View

20.

Yang L, Dan H, Sun M, Liu Q, Sun X, Feldman R . Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res. 2004; 64(13):4394-9. DOI: 10.1158/0008-5472.CAN-04-0343. View