Sur8/Shoc2 promotes cell motility and metastasis through activation of Ras-PI3K signaling

Abstract

// Saluja Kaduwal 1, 2 , Woo-Jeong Jeong 1, 2 , Jong-Chan Park 1, 2 , Kug Hwa Lee 1, 2 , Young-Mi Lee 1, 2, 5 , Soung-Hoo Jeon 1, 2, 6 , Yong-Beom Lim 1, 3 , Do Sik Min 1, 4 , Kang-Yell Choi 1, 2 1 Translational Research Center for Protein Function Control, Yonsei University, Seoul, 120-749, Korea 2 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749, Korea 3 Department of Materials Science and Engineering, Yonsei University, Seoul, 120-749, Korea 4 Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, 609-735, Korea 5 Current address: Division of Pharmacology and Translational Research, Hanmi Research Center, Hwaseong-si Gyeonggi-do, 445-813, Korea 6 Current address: Department of Microbiology and Immunology, Xenotransplantation Research Center, Medical Research Center, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, 110-799, Korea Correspondence to: Kang-Yell Choi, e-mail: kychoi@yonsei.ac.kr Keywords: Sur8, Ras, PI3K, cell migration, metastasis Received: June 02, 2015      Accepted: August 26, 2015      Published: September 05, 2015 ABSTRACT Sur8 (also known as Shoc2) is a Ras-Raf scaffold protein that modulates signaling through extracellular signal-regulated kinase (ERK) pathway. Although Sur8 has been shown to be a scaffold protein of the Ras-ERK pathway, its interaction with other signaling pathways and its involvement in tumor malignancy has not been reported. We identified that Sur8 interacts with the p110α subunit of phosphatidylinositol 3-kinase (PI3K), as well as with Ras and Raf, and these interactions are increased in an epidermal growth factor (EGF)- and oncogenic Ras-dependent manner. Sur8 regulates cell migration and invasion via activation of Rac and matrix metalloproteinases (MMPs). Interestingly, using inhibitors of MEK and PI3K we found Sur8 mediates these cellular behaviors predominantly through PI3K pathway. We further found that human metastatic melanoma tissues had higher Sur8 content followed by activations of Akt, ERK, and Rac. Lentivirus-mediated Sur8-knockdown attenuated metastatic potential of highly invasive B16-F10 melanoma cells indicating the role of Sur8 in melanoma metastasis. This is the first report to identify the role of scaffold protein Sur8 in regulating cell motility, invasion, and metastasis through activation of both ERK and PI3K pathways.