title: c-Cbl regulates αPix-mediated cell migration and invasion.
abstract: 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.
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Min Woo
authors.initials: MW
authors.lastname: Seong
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Ji Ho
authors.initials: JH
authors.lastname: Park
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Hee Min
authors.initials: HM
authors.lastname: Yoo
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Seung Wook
authors.initials: SW
authors.lastname: Yang
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Kyu Hee
authors.initials: KH
authors.lastname: Oh
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Seung Hyeun
authors.initials: SH
authors.lastname: Ka
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Dong Eun
authors.initials: DE
authors.lastname: Park
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Soon-Tae
authors.initials: ST
authors.lastname: Lee
authors.affiliation: School of Biological Sciences and Institute for Protein Metabolism, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: chchung@snu.ac.kr.
authors.forename: Chin Ha
authors.initials: CH
authors.lastname: Chung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000378:metabolism; D005816:Genetic Complementation Test; D005910:Glioma / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C576603:ARHGEF6 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D046988:Proteasome Endopeptidase Complex; C067419:CBL protein, human
keywords: Cell invasion; Cell migration; Glioma; c-Cbl; αPix