CLR-1 ENCODES A RECEPTOR TYROSINE PHOSPHATASE THAT NEGATIVELY REGULATES AN FGF RECEPTOR SIGNALING PATHWAY IN CAENORHABDITIS-ELEGANS

Receptor tyrosine phosphatases have been implicated in playing importa nt roles in cell signaling events by their ability to regulate the lev el of protein tyrosine phosphorylation. Although the catalytic activit y of their phosphatase domains has been well established, the biologic al roles of these molecules are, for the most part, not well understoo d. Here we show that the Caenorhabditis elegans protein CLR-1 (CLeaR) is a receptor tyrosine phosphatase (RTP) with a complex extracellular region and two intracellular phosphatase domains. Mutations in clr-l r esult in a dramatic Clr phenotype that we have used to study the physi ological requirements for the CLR-1 RTP. We show that the phosphatase activity of the membrane-proximal domain is essential for the in vivo function of CLR-1. By contrast, we present evidence that the membrane- distal domain is not required to prevent the Clr phenotype in vivo. Th e Clr phenotype of clr-1 mutants is mimicked by activation of the EGL- 15 fibroblast growth factor receptor (FGFR) and is suppressed by mutat ions that reduce or eliminate the activity of egl-15. Our data strongl y indicate that CLR-1 attenuates the action of an FGFR-mediated signal ing pathway by dephosphorylation.