P38γ MAPK Inflammatory and Metabolic Signaling in Physiology and Disease

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2023 Jul 14

PMID 37443708

Authors

Xiao-Mei Qi

Guan Chen

Affiliations

Soon will be listed here.

Abstract

p38γ MAPK (also called ERK6 or SAPK3) is a family member of stress-activated MAPKs and has common and specific roles as compared to other p38 proteins in signal transduction. Recent studies showed that, in addition to inflammation, p38γ metabolic signaling is involved in physiological exercise and in pathogenesis of cancer, diabetes, and Alzheimer's disease, indicating its potential as a therapeutic target. p38γphosphorylates at least 19 substrates through which p38γ activity is further modified to regulate life-important cellular processes such as proliferation, differentiation, cell death, and transformation, thereby impacting biological outcomes of p38γ-driven pathogenesis. P38γ signaling is characterized by its unique reciprocal regulation with its specific phosphatase PTPH1 and by its direct binding to promoter DNAs, leading to transcriptional activation of targets including cancer-like stem cell drivers. This paper will review recent findings about p38γ inflammation and metabolic signaling in physiology and diseases. Moreover, we will discuss the progress in the development of p38γ-specific pharmacological inhibitors for therapeutic intervention in disease prevention and treatment by targeting the p38γ signaling network.

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References

Qi X, Tang J, Loesch M, Pohl N, Alkan S, Chen G . p38gamma mitogen-activated protein kinase integrates signaling crosstalk between Ras and estrogen receptor to increase breast cancer invasion. Cancer Res. 2006; 66(15):7540-7. PMC: 2174269. DOI: 10.1158/0008-5472.CAN-05-4639. View

King Jr T, Bradford W, Castro-Bernardini S, Fagan E, Glaspole I, Glassberg M . A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370(22):2083-92. DOI: 10.1056/NEJMoa1402582. View

Hasegawa M, Cuenda A, Spillantini M, Thomas G, Cohen P, Goedert M . Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-syntrophin. A mechanism for specific substrate recognition. J Biol Chem. 1999; 274(18):12626-31. DOI: 10.1074/jbc.274.18.12626. View

Loesch M, Chen G . The p38 MAPK stress pathway as a tumor suppressor or more?. Front Biosci. 2008; 13:3581-93. PMC: 4758212. DOI: 10.2741/2951. View

Canovas B, Nebreda A . Diversity and versatility of p38 kinase signalling in health and disease. Nat Rev Mol Cell Biol. 2021; 22(5):346-366. PMC: 7838852. DOI: 10.1038/s41580-020-00322-w. View

Zhang J, Macartney T, Peggie M, Cohen P . Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3. Biochem J. 2017; 474(13):2235-2248. PMC: 5632801. DOI: 10.1042/BCJ20170288. View

Zhang X, Nam S, Wu J, Chen C, Liu X, Li H . Multi-Kinase Inhibitor with Anti-p38γ Activity in Cutaneous T-Cell Lymphoma. J Invest Dermatol. 2018; 138(11):2377-2387. PMC: 7269016. DOI: 10.1016/j.jid.2018.04.030. View

Kerk S, Papagiannakopoulos T, Shah Y, Lyssiotis C . Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment. Nat Rev Cancer. 2021; 21(8):510-525. PMC: 10257891. DOI: 10.1038/s41568-021-00375-9. View

Gonzalez-Teran B, Lopez J, Rodriguez E, Leiva L, Martinez-Martinez S, Bernal J . p38γ and δ promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation. Nat Commun. 2016; 7:10477. PMC: 5476828. DOI: 10.1038/ncomms10477. View

10.

Zhang X, Chen C, Li H, Hsiang J, Wu X, Hu W . Targeting the non-ATP-binding pocket of the MAP kinase p38γ mediates a novel mechanism of cytotoxicity in cutaneous T-cell lymphoma (CTCL). FEBS Lett. 2021; 595(20):2570-2592. PMC: 8577799. DOI: 10.1002/1873-3468.14186. View

11.

Qi X, Yin N, Ma S, Lepp A, Tang J, Jing W . p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion. Stem Cells. 2015; 33(9):2738-47. PMC: 4792188. DOI: 10.1002/stem.2068. View

12.

Cuenda A, Cohen P, Goedert M . Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO J. 1997; 16(2):295-305. PMC: 1169636. DOI: 10.1093/emboj/16.2.295. View

13.

Chen K, Lin S, Wu M, Ho M, Santhanam A, Chou C . Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation. Sci Signal. 2014; 7(347):ra98. DOI: 10.1126/scisignal.2005722. View

14.

Qi X, Zhi H, Lepp A, Wang P, Huang J, Basir Z . p38γ mitogen-activated protein kinase (MAPK) confers breast cancer hormone sensitivity by switching estrogen receptor (ER) signaling from classical to nonclassical pathway via stimulating ER phosphorylation and c-Jun transcription. J Biol Chem. 2012; 287(18):14681-91. PMC: 3340246. DOI: 10.1074/jbc.M112.349357. View

15.

Xu W, Liu R, Dai Y, Hong S, Dong H, Wang H . The Role of p38γ in Cancer: From review to outlook. Int J Biol Sci. 2021; 17(14):4036-4046. PMC: 8495394. DOI: 10.7150/ijbs.63537. View

16.

Gillespie M, Le Grand F, Scime A, Kuang S, von Maltzahn J, Seale V . p38-{gamma}-dependent gene silencing restricts entry into the myogenic differentiation program. J Cell Biol. 2009; 187(7):991-1005. PMC: 2806273. DOI: 10.1083/jcb.200907037. View

17.

Loesch M, Zhi H, Hou S, Qi X, Li R, Basir Z . p38gamma MAPK cooperates with c-Jun in trans-activating matrix metalloproteinase 9. J Biol Chem. 2010; 285(20):15149-15158. PMC: 2865276. DOI: 10.1074/jbc.M110.105429. View

18.

Tian Y, Yuan W, Fujita N, Wang J, Wang H, Shapiro I . Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. Am J Pathol. 2013; 182(6):2310-21. PMC: 3668031. DOI: 10.1016/j.ajpath.2013.02.037. View

19.

Kwong J, Hong L, Liao R, Deng Q, Han J, Sun P . p38alpha and p38gamma mediate oncogenic ras-induced senescence through differential mechanisms. J Biol Chem. 2009; 284(17):11237-46. PMC: 2670128. DOI: 10.1074/jbc.M808327200. View

20.

Mertens S, Craxton M, Goedert M . SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases. FEBS Lett. 1996; 383(3):273-6. DOI: 10.1016/0014-5793(96)00255-4. View