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.
(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,
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]