MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

Abstract

Hyperactivation of YAP has been commonly associated with tumorigenesis, and emerging evidence hints at multilayered Hippo-independent regulations of YAP. In this study, we identified a new MST4–YAP axis, which acts as a noncanonical Hippo signaling pathway that limits stress-induced YAP activation. MST4 kinase directly phosphorylated YAP at Thr83 to block its binding with importin α, therefore leading to YAP cytoplasmic retention and inactivation. Due to a consequential interplay between MST4-mediated YAP phospho-Thr83 signaling and the classical YAP phospho-Ser127 signaling, the phosphorylation level of YAP at Thr83 was correlated to that at Ser127. Mutation of T83E mimicking MST4-mediated alternative signaling restrained the activity of both wild-type YAP and its S127A mutant mimicking loss of classical Hippo signal. Depletion of MST4 in mice promoted gastric tumorigenesis with diminished Thr83 phosphorylation and hyperactivation of YAP. Moreover, loss of MST4–YAP signaling was associated with poor prognosis of human gastric cancer. Collectively, our study uncovered a noncanonical MST4–YAP signaling axis essential for suppressing gastric tumorigenesis.

Hippo-Independent Regulation of Yki/Yap/Taz: A Non-canonical View

“…For example, Nuclear Dbf2-related kinases, NDR1 and NDR2, which are structurally related to Lats1/2, can phosphorylate Yap on the same set of sites as Lats1/2 in the intestine epithelium ( Zhang L. et al, 2015 ). MST4, which is closely related to MST1/2, binds and phosphorylates Yap at Thr83 to inhibit Yap nuclear import and activity independent of the canonical Hippo pathway ( An et al, 2020 ). Deletion of MST4 in mice diminished Yap Thr83 phosphorylation, increased Yap activity, and promoted gastric tumorigenesis ( An et al, 2020 ).…”

“…MST4, which is closely related to MST1/2, binds and phosphorylates Yap at Thr83 to inhibit Yap nuclear import and activity independent of the canonical Hippo pathway ( An et al, 2020 ). Deletion of MST4 in mice diminished Yap Thr83 phosphorylation, increased Yap activity, and promoted gastric tumorigenesis ( An et al, 2020 ). Furthermore, loss of MST4 and YapThr83 phosphorylation is associated with poor prognosis of human gastric cancer ( An et al, 2020 ).…”

“…Deletion of MST4 in mice diminished Yap Thr83 phosphorylation, increased Yap activity, and promoted gastric tumorigenesis ( An et al, 2020 ). Furthermore, loss of MST4 and YapThr83 phosphorylation is associated with poor prognosis of human gastric cancer ( An et al, 2020 ). In response to inflammatory cytokine, TAK1 binds and phosphorylates Yap/Taz independent of Lats1/2 to promote Yap/Taz degradation, which alleviates the inhibition of NFκB, leading to the induction of matrix-degrading enzymes and subsequently cartilage degradation during osteoarthritis pathogenesis ( Deng et al, 2018 ).…”

Yes-Associated Protein 1: Role and Treatment Prospects in Orthopedic Degenerative Diseases

“…In recent years, research on YAP1 has increased, especially with respect to tumors. YAP1 has been confirmed to be overexpressed in a variety of tumors, including gastric tumors ( An et al, 2020 ), liver tumors ( Bisso et al, 2020 ), ovarian cancer ( Munoz-Galvan et al, 2020 ), and breast cancer ( Song et al, 2018 ), suggesting that YAP1 has a role as a candidate oncogene in tumorigenesis. In addition, YAP1 also plays an important role in the migration and invasion of melanoma and osteosarcoma ( Zucchini et al, 2019 ; Luo et al, 2020 ).…”

<p><em>MST4</em> Regulates Epithelial–Mesenchymal Transition of Choriocarcinoma by Mediating TGF-β1 Expression</p>

“…10 Studies have illustrated that MST4 phosphorylated YAP to suppress YAP activation in the Hippo pathway. 22 Biofunction of MST4 in choriocarcinoma is different from other tumors. It is fascinating that MST4 was more lowly expressed in choriocarcinoma lesions than in normal villus.…”