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STK25 suppresses Hippo signaling by regulating SAV1-STRIPAK antagonism.

ABSTRACT: The MST-LATS kinase cascade is central to the Hippo pathway that controls tissue homeostasis, development, and organ size. The PP2A complex STRIPAK^SLMAP blocks MST1/2 activation. The GCKIII family kinases associate with STRIPAK, but the functions of these phosphatase-associated kinases remain elusive. We previously showed that the scaffolding protein SAV1 promotes Hippo signaling by counteracting STRIPAK (Bae et al., 2017). Here, we show that the GCKIII kinase STK25 promotes STRIPAK-mediated inhibition of MST2 in human cells. Depletion of STK25 enhances MST2 activation without affecting the integrity of STRIPAK^SLMAP. STK25 directly phosphorylates SAV1 and diminishes the ability of SAV1 to inhibit STRIPAK. Thus, STK25 as the kinase component of STRIPAK can inhibit the function of the STRIPAK inhibitor SAV1. This mutual antagonism between STRIPAK and SAV1 controls the initiation of Hippo signaling.

SUBMITTER: Bae SJ

PROVIDER: S-EPMC7182433 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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STK25 suppresses Hippo signaling by regulating SAV1-STRIPAK antagonism.

Bae Sung Jun SJ Ni Lisheng L Luo Xuelian X

eLife 20200415

The MST-LATS kinase cascade is central to the Hippo pathway that controls tissue homeostasis, development, and organ size. The PP2A complex STRIPAK<sup>SLMAP</sup> blocks MST1/2 activation. The GCKIII family kinases associate with STRIPAK, but the functions of these phosphatase-associated kinases remain elusive. We previously showed that the scaffolding protein SAV1 promotes Hippo signaling by counteracting STRIPAK (Bae et al., 2017). Here, we show that the GCKIII kinase STK25 promotes STRIPAK-m ...[more]

PMID: 32292165

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Project description:BackgroundEmerging evidence has shown that exosome microRNAs (miRNAs) regulate the development of hepatocellular carcinoma (HCC). Here, the influences of miR-4800-3p on the progression of HCC were explored.Materials and methodsThe expression of miR-4800-3p in the exosome derived by transforming growth factor beta 1 (TGF-β1)-treated HCC cells and the serum exosome isolated from HCC patients were identified by real-time PCR. The effects of TGF-β1 and the influences of Huh7-secreted exosomes and the effects of miR-4800-3p combined with/without STK25 on cell functions were explored using the EdU assay cloning experiments, wound healing assay, and Transwell assay. The corresponding molecular mechanisms were further detected using Western blot and real-time PCR assays. The combination of miR-4800-3p and STK25 was verified by the dual-luciferase and RNA pulldown assays. The influences of miR-4800-3p on the growth and epithelial-mesenchymal transformation (EMT) of implanted tumors were tested in vivo and further confirmed by Western blot.ResultsThe miR-4800-3p expression was highly expressed in both exosomes derived by TGF-β1-treated HCC cells and the serum exosomes of HCC patients. In the cases of treatment with both Huh7-derived exosomes, the level of miR-4800-3p expression was highest, and the treatment of TGF-β1 could greatly promote the proliferation, stemness, migration, and invasion of HCC cells via upregulating the markers of stemness and EMT, including CD44, CD133, OCT4, N-cadherin, E-cadherin, and ZO-1. Similar results could be obtained when miR-4800-3p was overexpressed in HCC cells. Furthermore, downregulation of STK25 expression, a direct target gene of miR-4800-3p, could greatly rescue the malignant biological behaviors aggravated by overexpression of miR-4800-3p. This was achieved by suppressing the expression of CD44, CD133, OCT4, N-cadherin, and PCNA and activating the Hippo pathway while increasing E-cadherin and ZO-1. Similar results were also obtained in vivo that knockdown of miR-4800-3p expression suppressed tumor growth induced by Huh7-derived exosomes by mediating the EMT markers and the Hippo signaling pathway.ConclusionExosomal miR-4800-3p could accelerate HCC development by regulating the Hippo signal by targeting STK25, which could be used as a new therapeutic target for HCC treatment.

Dataset Information

STK25 suppresses Hippo signaling by regulating SAV1-STRIPAK antagonism.

Publications

STK25 suppresses Hippo signaling by regulating SAV1-STRIPAK antagonism.

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