Growth Factor Receptors

Ubiquitin May Signal Degradation in Two Ways

Science's STKE  11 Jan 2000:
Vol. 2000, Issue 14, pp. tw3
DOI: 10.1126/stke.2000.14.tw3

The intracellular adaptor protein c-Cbl has been implicated in the ubiquitination and degradation of certain growth factor receptors. Lill et al. and Levkowitz et al. have now determined that interaction between the the src homogy 2 (SH2) domain of c-Cbl and the tail of activated epidermal growth factor receptor (EGFR) is essential for this effect. Levkowitz et al. further identified a tyrosine residue in the EGFR tail that serves as the c-Cbl docking site and also found that c-Cbl itself became phosphorylated by the receptor at a specific tyrosine as well. Phosphorylation of c-Cbl was required for ubiquitination of activated EGFR, suggesting that the adaptor protein could act as a ubiquitin ligase. Furthermore, ubiquitination may play a critical role in sorting activated growth factor receptors to the lysosomal degradation pathway. Both groups report that when EGFR interaction with c-Cbl was defective, the receptor was not downregulated. Levkowitz et al. noted that although activated EGFRs were neither ubiquitinated nor degraded, they were still internalized, but recycled to the cell surface. Ubiquitination of growth factor receptors by this mechanism could ensure receptor downregulation by directing receptor degradation by both proteosomal and lysosomal enzymes.

Levkowitz, G., Waterman, H., Ettenberg, S.A., Katz, M., Tsygankov, A.Y., Alroy, I., Lavi, S., Iwai, K., Reiss, Y., Ciechanover, A., Lipkowitz, S., and Yarden, Y. (1999) Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol. Cell 4: 1029-1040. [Online Journal]

Lill, N.L., Douillard, P., Awwad, R.A., Ota, S., Lupher Jr., M.L., Miyake, S., Meissner-Lula, N., Hsu, V.W., and Band, H. (2000) The evolutionarily conserved N-terminal region of Cbl is sufficient to enhance down-regulation of the epidermal growth factor receptor. J. Biol. Chem. 275: 367-377. [Abstract] [Full Text]