Other Major Types of Signaling Mediators

Thiriet, Marc

doi:10.1007/978-1-4614-4370-4_10

Cited by 1 publication

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“…[25,33,[40][41][42][43] The regulatory domain of MST3, MST4, and STK25 lies at the C-terminal to the catalytic domain and carries a putative bipartite nuclear localization signal at its N-terminal end, which is relatively well conserved (Figure 1). [44,45] This sequence is followed by a variable region of 119-134 residues (about 20% similarity in amino acid sequence), which is predicted to be highly disordered and is suggested to interact with various signaling molecules and regulatory proteins. [25,30] As an example, the regulatory domain of all three GCKIIIs has been shown to heterodimerize with PDCD10 (programmed cell death 10, also known as CCM3).…”

Section: Domain Structure Of the Human Gcki II Subfamily Of Ste20 Kin...mentioning

confidence: 99%

GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond

et al. 2022

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Nonalcoholic fatty liver disease (NAFLD) is defined by excessive accumulation of lipid droplets within hepatocytes. The STE20-type kinases comprising the germinal center kinase III (GCKIII) subfamily -MST3, MST4, and STK25 -decorate intrahepatocellular lipid droplets and have recently emerged as critical regulators of the initiation and progression of NAFLD. While significant advancement has been made toward deciphering the role of GCKIII kinases in hepatic fat accumulation (i.e., steatosis) as well as the aggravation of NAFLD into its severe form nonalcoholic steatohepatitis (NASH), much remains to be resolved. This review provides a brief overview of the recent studies in patient cohorts, cultured human cells, and mouse models, which have characterized the function of MST3, MST4, and STK25 in the regulation of hepatic lipid accretion, meta-inflammation, and associated cell damage in the context of NAFLD/NASH. We also highlight the conflicting data and emphasize future research directions that are needed to advance our understanding of GCKIII kinases as potential targets in the therapy of NAFLD and its comorbidities. Conclusions: Several lines of evidence suggest that GCKIII proteins govern the susceptibility to hepatic lipotoxicity and that pharmacological inhibition of these kinases could mitigate NAFLD development and aggravation. Comprehensive characterization of the molecular mode-of-action of MST3, MST4, and STK25 in hepatocytes as well as extrahepatic tissues is important, especially in relation to their impact on carcinogenesis, to fully understand the efficacy as well as safety of GCKIII antagonism.

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