RhoA GTPase phosphorylated at tyrosine 42 by src kinase binds to β-catenin and contributes transcriptional regulation of vimentin upon Wnt3A

• Published in: Redox biology Vol. 40; p. 101842
• Main Authors: Kim, Jae-Gyu, Mahmud, Shohel, Min, Jung Ki, Lee, Yoon-Beom, Kim, Hyunbin, Kang, Dong-Chul, Park, Hwee-Seon, Seong, Jihye, Park, Jae-Bong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2021; Elsevier
• Subjects: Cancer; GSK-3β; p-Tyr42 RhoA; Research Paper; Src; Superoxide; Wnt3A; β-Catenin; GSK-3β; Src; Wnt3A; p-Tyr42 RhoA; β-Catenin; Superoxide; Cancer
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2020.101842

In the Wnt canonical pathway, Wnt3A has been known to stabilize β-catenin. In the non-canonical Wnt signaling pathway, Wnt is known to activate Rho GTPases. The correlation between canonical and non-canonical pathways by Wnt signaling, however, has not been well elucidated. Here, we identified that Wnt3A promoted superoxide generation, leading to Tyr42 phosphorylation of RhoA through activations of c-Src and Rho-dependent coiled coil kinase 2 (ROCK2) and phosphorylation of p47phox, a component of NADPH oxidase. Wnt3A also induced accumulation of β-catenin along with activations of RhoA and ROCK1. Concurrently, ROCK1 was able to phosphorylate GSK-3β at Ser9, which phosphorylated Src at Ser51 and Ser492 residues, leading to Src inactivation through dephosphorylation of Tyr416 during the late period of Wnt3A treatment. Meanwhile, p-Tyr42 RhoA bound to β-catenin via the N-terminal domain of β-catenin, thereby leading to the nuclear translocation of p-Tyr42 RhoA/β-catenin complex. Notably, p-Tyr42 RhoA as well as β-catenin was associated with the promoter of Vim, leading to increased expression of vimentin. In addition, stomach cancer patients harboring higher expressed p-Tyr42 Rho levels revealed the much poorer survival probability. Therefore, we propose that p-Tyr42 RhoA is crucial for transcriptional regulation of specific target genes in the nucleus by binding to their promoters and involved in tumorigenesis. [Display omitted] •ROCK2 phosphorylates p47phox, a component of NADPH oxidase, leading to superoxide production upon Wnt3A.•Wnt3A upregulates not only β-catenin but also p-Tyr42 RhoA through Src, which is activated by superoxide.•p-Tyr42 RhoA/β-catenin complex translocates to nucleus and binds to the promoter of Vim, leading to vimentin expression.•ROCK1 phosphorylates GSK-3β at Ser9, resulting in Ser493 and Ser51 phosphorylation of Src and its inactivation for desensitizing Wnt3A.•Cancer patients harboring high p-Tyr42 RhoA level reveal the much poorer survival probability.