MOLECULAR ANALYSIS OF
clr-1, A NEGATIVE REGULATOR OF THE FGFR IN C. elegans. Michelle Kokel, Leslie DeLong, and Michael J. Stern, Department of Genetics, Yale University, New Haven CT 06536, USA The
egl-15 encoded fibroblast growth factor receptor (FGFR) tyrosine kinase mediates multiple biological processes in C. elegans.
egl-15 activity is required for viability, proper sex myoblast migration, and the expression of the Clear phenotype of
clr-1 mutants. Genetic analysis suggests that
clr-1 acts as a negative regulator of some of the activities of
egl-15. In order to understand this interaction at the molecular level, we cloned and sequenced
clr-1 and found that it encodes a receptor-linked protein tyrosine phosphatase (PTP). This suggests that CLR-1 regulates signaling through the FGFR either by dephosphorylation of EGL-15 directly, or of another component of the
egl-15 signaling pathway. Thus, the Clear phenotype seems to be due to hyperactivity of FGFR signaling, perhaps due to increased tyrosine phosphorylation. There are a number of models which may explain why
clr-1 only appears to affect a subset of
egl-15 phenotypes. One possibility is that PTP activity is specific. For example, CLR-1 may only act on specific tyrosine residues in EGL-15 or downstream signaling components involved in specific pathways. Another possibility is that egl- 15 has different functions in different tissues and that
clr-1 is only expressed in a subset of these tissues. To distinguish between these two possibilities, we plan to use antibody staining to determine the expression patterns of
clr-1 and
c91-15. The antibodies should also be useful to study the interaction of these two molecules biochemically. Suppressors of
clr-1 (Soc) have identified three genes that could encode activators or mediators of
egl-15 activity. One of these genes,
sem-5, encodes an SH2/SH3 containing adaptor protein required to transduce signals from a variety of receptor tyrosine kinases. The function of SEM-5 supports the hypothesis that
clr-1 suppressors may mediate signaling through the FGFR. Thus, we have begun to clone the other two soc genes with the hope that their analysis will provide additional insights into FGFR mediated signaling pathways.