WNT5a Signaling through ROR2 Activates the Hippo Pathway to Suppress YAP1 Activity and Tumor Growth

Abstract

Noncanonical Wnt signaling by WNT5a has oncogenic and tumor suppressive activities, but downstream pathways mediating these specific effects remain to be fully established. In a subset of prostate cancer organoid culture and xenograft models, inhibition of Wnt synthesis stimulated growth, while WNT5a or a WNT5a mimetic peptide (Foxy5) markedly suppressed tumor growth. WNT5a caused a ROR2-dependent decrease in YAP1 activity that was associated with increased phosphorylation of MST1/2, LATS1, MOB1, and YAP1, indicating Hippo pathway activation. Deletion of MST1/2 abrogated the WNT5a response. WNT5a similarly activated Hippo in ROR2-expressing melanoma cells, while WNT5a in ROR2-negative cells suppressed Hippo. This suppression was associated with increased inhibitory phosphorylation of NF2/Merlin that was not observed in ROR2-expressing cells. WNT5a also increased mRNA encoding Hippo pathway components including MST1 and MST2 and was positively correlated with these components in prostate cancer clinical datasets. Conversely, ROR2 and WNT5a expression were stimulated by YAP1, and correlated with increased YAP1 activity in clinical datasets, revealing a WNT5a/ROR2 negative feedback loop to modulate YAP1 activity. Together these findings identify Hippo pathway activation as a mechanism that mediates the tumor suppressive effects of WNT5a and indicate that expression of ROR2 may be a predictive biomarker for responsiveness to WNT5a-mimetic drugs.

Low expression of PRRG2 in kidney renal clear cell carcinoma: an immune infiltration-associated prognostic biomarker

“…Therefore, the interaction and regulatory relationship between YAP1 and AMOTL1 are of significant importance for comprehending the mechanisms of cellular biology and tumorigenesis. Additionally, YAP1 can participate in the occurrence and progression of tumors by regulating various signaling pathways, such as MAPK, AKT, and Hippo [ 30 – 32 ]. Under normal circumstances, the activity of YAP1 is suppressed by the Hippo signaling pathway.…”

m6A‐induced TRIB3 regulates Hippo pathway through interacting with LATS1 to promote the progression of lung adenocarcinoma

“…The Hippo pathway, a conserved signaling cascade, plays a critical role in maintaining tissue homeostasis, regulating organ size, and suppressing tumor growth (Dey et al, 2020; Fu et al, 2022; Ma, Meng, et al, 2019). Dysregulation of the Hippo pathway has been implicated in various types of cancer, including lung cancer (Tang et al, 2023; Wang, Ma, et al, 2023; Wang, Yu, et al, 2023; Zhang et al, 2023). Dysregulation of the Hippo/Yes‐associated protein (YAP) axis has been shown to contribute to tumor progression and therapy resistance in various cancer types, including LUAD.…”

YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling

“…This pathway is well-described in embryogenesis, where it initiates downstream activation of the c-Jun N-terminal kinase (JNK) signaling and the Rho/Rac guanosine triphosphate hydrolases (GTPases), including Rho-kinase (ROCK) [ 8 ]. Recent studies have proposed that Wnt5a activates non-canonical Wnt signaling via receptor tyrosine kinase-like orphan receptor (RoR) proteins [ 9 ]. Subsequent investigations have affirmed that Wnt5a-receptor tyrosine kinase-like orphan receptor 2 (RoR2) signaling amplifies JNK activation and recruitments of c-Jun to the receptor activator of NF-kappaB (RANK) gene promoter, thereby enhancing the Wnt/JNK pathway-induced signal cascade and activating JNK phosphorylation [ 10 ].…”