Stabilization of Sur8 via PKCα/δ degradation promotes transformation and migration of colorectal cancer cells
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Kug Hwa Lee1,2, Woo-Jeong Jeong1,2, Pu-Hyeon Cha1,2, Sang-Kyu Lee1,2, Do Sik Min1,3 and Kang-Yell Choi1,2
1Translational Research Center for Protein Function Control, Yonsei University, Seoul, South Korea
2Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
3Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, South Korea
Kang-Yell Choi, email: [email protected]
Keywords: Sur8; fibroblast growth factor-2; protein kinase C α/δ; Ras signaling; colorectal cancer
Received: July 15, 2017 Accepted: December 03, 2017 Published: December 14, 2017
Scaffold proteins of the mitogen activated protein kinase (MAPK) pathway recruit protein kinase cascades to confer context-specificity to cellular signaling. Varying concentrations of scaffold proteins determine different aspects of signaling outputs. However, regulatory mechanisms of scaffold proteins are poorly understood. Sur8, a scaffold protein in the Ras-MAPK pathway, is known to be involved in cell transformation and migration, and is increased in human colorectal cancer (CRC) patient tissue. Here we determine that regulation of Sur8 stability mediates transformation and migration of CRC cells. Fibroblast growth factor 2 (FGF2) is identified as an external regulator that stabilizes Sur8. Protein kinase C-alpha and -delta (PKCα/δ) are also identified as specific mediators of FGF2 regulation of Sur8 stability. PKCα/δ phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. Sur8 mutations, which mimic phosphorylation by PKCα/δ and destabilized Sur8, suppress the FGF2-induced transformation and migration of CRC cells. The clinical relevance of Sur8 regulation by PKCα/δ is indicated by the inverse relationship between PKCα/δ and Sur8 expression in human CRC patient tissues. Overall, our findings demonstrate for the first time a regulatory mechanism of Sur8 stability involving cellular transformation and migration in CRC.
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