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Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation

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A Corrigendum to this article was published on 14 October 2004

Abstract

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.

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Abbreviations

SH 2/3:

Src homology 2/3

EGFR:

epidermal growth factor receptor

PDGER:

platelet-derived growth factor receptor

PI3-K:

phosphatidylinositol 3-kinase

STAT3:

signal transducers and activators of transcription 3

PY:

phosphotyrosine

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Acknowledgements

We thank Y Yoshida and T Yasuda for valuable discussion and technical advice. We thank W Langdon (University of Western Australia), S Lipkowitz (NCI), and M Yokouchi (University of Kagoshima) for cDNAs, T Kitamura (University of Tokyo) for the retrovirus system, and K Iwai (Osaka City University) for mouse E1. We thank T Suzuki and T Chiba (Tokyo Metro. Inst. of Med. Sci.) for critical discussion. This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. MK is a recipient of the Japanese government scholarship.

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Authors and Affiliations

  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

    Minsoo Kim, Tohru Tezuka & Tadashi Yamamoto

  2. Department of Molecular Oncology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8613, Japan

    Keiji Tanaka

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  1. Minsoo Kim
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  2. Tohru Tezuka
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Correspondence to Tadashi Yamamoto.

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Kim, M., Tezuka, T., Tanaka, K. et al. Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Oncogene 23, 1645–1655 (2004). https://doi.org/10.1038/sj.onc.1207298

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