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Requirements of Multiple Domains of SLI-1, a Caenorhabditis elegans Homologue of c-Cbl, and an Inhibitory Tyrosine in LET-23 in Regulating Vulval Differentiation

Yoon, Charles H. and Chang, Chieh and Hopper, Neil A. and Lesa, Giovanni M. and Sternberg, Paul W. (2000) Requirements of Multiple Domains of SLI-1, a Caenorhabditis elegans Homologue of c-Cbl, and an Inhibitory Tyrosine in LET-23 in Regulating Vulval Differentiation. Molecular Biology of the Cell, 11 (11). pp. 4019-4031. ISSN 1059-1524.

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SLI-1, a Caenorhabditis elegans homologue of the proto-oncogene product c-Cbl, is a negative regulator of LET-23-mediated vulval differentiation. Lack of SLI-1 activity can compensate for decreased function of the LET-23 epidermal growth factor receptor, the SEM-5 adaptor, but not the LET-60 RAS, suggesting that SLI-1 acts before RAS activation. SLI-1 and c-Cbl comprise an N-terminal region (termed SLI-1:N/Cbl-N, containing a four-helix bundle, an EF hand calcium-binding domain, and a divergent SH2 domain) followed by a RING finger domain and a proline-rich C-terminus. In a transgenic functional assay, the proline-rich C-terminal domain is not essential for sli-1(+) function. A protein lacking the SH2 and RING finger domains has no activity, but a chimeric protein with the SH2 and RING finger domains of SLI-1 replaced by the equivalent domains of c-Cbl has activity. The RING finger domain of c-Cbl has been shown recently to enhance ubiquitination of active RTKs by acting as an E3 ubiquitin-protein ligase. We find that the RING finger domain of SLI-1 is partially dispensable. Further, we identify an inhibitory tyrosine of LET-23 requiring sli-1(+) for its effects: removal of this tyrosine closely mimics the loss of sli-1 but not of another negative regulator, ark-1. Thus, we suggest that this inhibitory tyrosine mediates its effects through SLI-1, which in turn inhibits signaling upstream of LET-60 RAS in a manner not wholly dependent on the ubiquitin-ligase domain.

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Additional Information:Copyright © 2000 by The American Society for Cell Biology Submitted June 28, 2000; Revised August 21, 2000; Accepted September 15, 2000. We thank Michael Stern for providing the sem-5(ay73) and the sem-5(n1619) alleles, Wally Langdon for providing the human c-cbl cDNA. We also thank Raffi Aroian for critical reading of this manuscript; Pepe Alberola-I1a, David Chan, Maureen Barr, anonymous reviewers, and members of the Sternberg laboratory for helpful comments. This work was supported by a grant from the US Army Breast Cancer Program (grant DAMD-95-1-5003) to P.W.S., an investigator with the Howard Hughes Medical Institute. C.H.Y. and C.C. were funded with a National Institutes of Health predoctoral training grant (GM07616). Some strains were provided by the Caenorhabditis Genetic Center.
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Deposited On:05 Jan 2007
Last Modified:26 Dec 2012 09:28

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