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			PubMed Journals: Oncogene

  Source:		PMID: 14661060


    		Oncogene. 2004 Mar 4;23(9):1645-55.
     
			Cbl-c suppresses v-Src-induced transformation
			through ubiquitin-dependent protein degradation.

			Kim M(1), Tezuka T, Tanaka K, Yamamoto T.

			Author Information
			(1) Division of Oncology, Department of
			Cancer Biology, The Institute of Medical
			Science, The University of Tokyo, 4-6-1
			Shirokanedai, Minato-ku, Tokyo 108-8639,
			Japan.

			Erratum in Oncogene. 2004 Oct 14;23(47):7903-4.

			The Cbl family proteins Cbl, Cbl-b, and
			Cbl-c/Cbl-3 are thought to regulate signaling
			through protein-tyrosine kinases, positively
			as scaffold proteins and negatively as ubiquitin
			ligases. However, the precise signaling
			pathways and target proteins for each Cbl
			family member are not well understood. Here
			we show that Src is a preferential target
			of Cbl-c for degradation. Although exogenous
			expression of all Cbl family proteins suppressed
			the anchorage-independent growth of
			v-Src-transformed NIH3T3 cells, only Cbl-c
			caused reversion of the refractile morphology.
			The level of v-Src protein was reduced by
			Cbl-c, possibly through a lysosome-dependent
			pathway. The TKB domain and RING finger
			of Cbl-c were important for its antioncogenic
			activity. Wild-type Cbl-c promoted ubiquitination
			of Src in 293T cells, whereas a RING finger
			mutant did not. Cbl-c bound specifically
			to Src phosphorylated at Tyr419. Furthermore,
			Cbl-c together with UbcH5 induced ubiquitination
			of Src in vitro. Importantly, the Tyr419
			nonphosphorylated form of Src was not ubiquitinated
			by Cbl-c. Therefore, activated Src may be
			a direct target of Cbl-c in vivo. Our results
			suggest that Cbl and Cbl-b suppress v-Src-induced
			transformation through mechanisms distinct
			from that of Cbl-c.

			DOI: 10.1038/sj.onc.1207298 PMID: 14661060
			[Indexed for MEDLINE]

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