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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. PMCID PMC15054.

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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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Sternberg, Paul W.0000-0002-7699-0173
Additional Information:Copyright © 2000 by The American Society for Cell Biology. Under the License and Publishing Agreement, authors grant to the general public, effective two months after publication of (i.e.,. the appearance of) the edited manuscript in an online issue of MBoC, the nonexclusive right to copy, distribute, or display the manuscript subject to the terms of the Creative Commons–Noncommercial–Share Alike 3.0 Unported license ( 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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Army Research Office (ARO)DAMD-95-1-5003
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIH Predoctoral Training GrantGM07616
PubMed Central ID:PMC15054
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ID Code:7036
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Deposited On:05 Jan 2007
Last Modified:22 Sep 2015 19:14

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