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Sur8 mediates tumorigenesis and metastasis in colorectal cancer
이영미,Saluja Kaduwal,이국화,박종찬,정우정,최강열 생화학분자생물학회 2016 Experimental and molecular medicine Vol.48 No.-
Sur8, a scaffold protein of the Ras pathway, interacts with Ras and Raf and modulates the Ras-extracellular signal-regulated kinase (ERK) pathway. Here we show that Sur8 is overexpressed in established human colorectal cancer (CRC) cell lines and CRC patient tissues. Moreover, Sur8 expression is increased during liver metastasis in CRC patients. Sur8 knockdown decreases ERK and Akt activities in CRC cell lines, regardless of their K-Ras, B-Raf or PI3K mutation status. Overexpression or knockdown of Sur8 increases or decreases, respectively, the proliferation or transformation of CRC cell lines. Sur8 knockdown attenuates the migration and invasion of HCT116 CRC cells. Subcutaneous or orthotopic injection of HCT116 cells harboring a doxycycline (Dox)-mediated Sur8 knockdown system in nude mice resulted in decreased tumorigenic potential and inhibited the liver metastatic potential of HCT116 cells. Taken together, our data support the role of Sur8 as a promoter of tumorigenesis and liver metastasis in CRC through its modulation of the Ras-ERK and PI3K-Akt signaling pathways.
Jeong, W.-J.,Yoon, J.,Park, J.-C.,Lee, S.-H.,Lee, S.-H.,Kaduwal, S.,Kim, H.,Yoon, J.-B.,Choi, K.-Y. American Association for the Advancement of Scienc 2012 Science signaling Vol.5 No.219
<P>Although the guanosine triphosphate/guanosine diphosphate loading switch is a major regulatory mechanism that controls the activity of the guanosine triphosphatase Ras, we report a distinct mechanism for regulating Ras activity through phosphorylation-mediated degradation and describe the role of this second regulatory mechanism in the suppression of cellular transformation and tumors induced by Ras mutations. We found that negative regulators of Wnt/beta-catenin signaling contributed to the polyubiquitin-dependent degradation of Ras after its phosphorylation by glycogen synthase kinase 3 beta (GSK3 beta) and the subsequent recruitment of beta-TrCP-E3 ligase. We found a positive association between tumorigenesis and Ras stabilization resulting from the aberrant activation of Wnt/beta-catenin signaling in adenomas from two mouse models of colon cancer, human colonic tumors from various stages, and colon polyps of patients with familial adenomatous polyposis. Our results indicated that GSK3 beta plays an essential role in Ras degradation and that inhibition of this degradation pathway by aberrant Wnt/beta-catenin signaling may contribute to Ras-induced transformation in colorectal tumorigenesis.</P>
Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation
Cha, Pu-Hyeon,Cho, Yong-Hee,Lee, Sang-Kyu,Lee, JaeHeon,Jeong, Woo-Jeong,Moon, Byoung-San,Yun, Ji-Hye,Yang, Jee Sun,Choi, Sooho,Yoon, Juyong,Kim, Hyun-Yi,Kim, Mi-Yeon,Kaduwal, Saluja,Lee, Weontae,Min, Nature Publishing Group, a division of Macmillan P 2016 Nature chemical biology Vol.12 No.8
Both the Wnt/β-catenin and Ras pathways are aberrantly activated in most human colorectal cancers (CRCs) and interact cooperatively in tumor promotion. Inhibition of these signaling may therefore be an ideal strategy for treating CRC. We identified KY1220, a compound that destabilizes both β-catenin and Ras, via targeting the Wnt/β-catenin pathway, and synthesized its derivative KYA1797K. KYA1797K bound directly to the regulators of G-protein signaling domain of axin, initiating β-catenin and Ras degradation through enhancement of the β-catenin destruction complex activating GSK3β. KYA1797K effectively suppressed the growth of CRCs harboring APC and KRAS mutations, as shown by various in vitro studies and by in vivo studies using xenograft and transgenic mouse models of tumors induced by APC and KRAS mutations. Destabilization of both β-catenin and Ras via targeting axin is a potential therapeutic strategy for treatment of CRC and other type cancers activated Wnt/β-catenin and Ras pathways.