c-Cbl regulates αPix-mediated cell migration and invasion.
Min Woo Seong, Ji Ho Park, Hee Min Yoo, Seung Wook Yang, Kyu Hee Oh, Seung Hyeun Ka, Dong Eun Park, Soon-Tae Lee, Chin Ha Chung
Author Information
Min Woo Seong: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
Ji Ho Park: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
Hee Min Yoo: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
Seung Wook Yang: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
Kyu Hee Oh: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
Seung Hyeun Ka: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
Dong Eun Park: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
Soon-Tae Lee: Department of Neurology, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
Chin Ha Chung: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: chchung@snu.ac.kr.
c-Cbl, a RING-type ubiquitin E3 ligase, down-regulates receptor tyrosine kinases, including EGF receptor, and inhibits cell proliferation. Moreover, c-Cbl mutations are frequently found in patients with myeloid neoplasm. Therefore, c-Cbl is known as a tumor suppressor. αPix is expressed only in highly proliferative and mobile cells, including immune cells, and up-regulated in certain invasive tumors, such as glioblastoma multiforme. Here, we showed that c-Cbl serves as an ubiquitin E3 ligase for proteasome-mediated degradation of αPix, but not βPix. Remarkably, the rat C6 and human A172 glioma cells were unable to express c-Cbl, which leads to a dramatic accumulation of αPix. Depletion of αPix by shRNA markedly reduced the ability of the glioma cells to migrate and invade, whereas complementation of shRNA-insensitive αPix promoted it. These results indicate that c-Cbl negatively regulates αPix-mediated cell migration and invasion and the lack of c-Cbl in the C6 and A172 glioma cells is responsible for their malignant behavior.
