Stabilization of Sur8 via PKCα/δ degradation promotes transformation and migration of colorectal cancer cells

// Kug Hwa Lee 1, 2 , Woo-Jeong Jeong 1, 2 , Pu-Hyeon Cha 1, 2 , Sang-Kyu Lee 1, 2 , Do Sik Min 1, 3 and Kang-Yell Choi 1, 2 1 Translational Research Center for Protein Function Control, Yonsei University, Seoul, South Korea 2 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea 3 Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, South Korea Correspondence to: Kang-Yell Choi, email: kychoi@yonsei.ac.kr 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 ABSTRACT 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.