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Submitted on March 7, 2003
Accepted on September 26, 2003
1 Flanders Interuniversity Institute for Biotechnology, Department of Medical Protein Research (VIB09), Ghent University, Belgium.
* To whom correspondence should be addressed. E-mail: Jan.Tavernier{at}rug.ac.be.
The leptin receptor (LR), a member of the class I cytokine receptor family, is composed of a single subunit. Its extracellular domain consists of two so-called cytokine receptor homology (CRH) domains, separated by an immunoglobulin-like (Ig-like) domain, and two additional fibronectin type III (FN III) modules. Requirements for LR activation were examined using a complementation strategy. Two LR mutants, LR-FFY-
box1 and LR-F3, deficient in JAK or STAT activation respectively, were only capable to generate a STAT3-dependent signal when co-expressed. Based on the requirements for JAK/STAT signaling, and on the lack of complementation with similar receptor constructs, but containing the extracellular domain of the homodimeric erythropoietin receptor (EpoR), this observation can only be explained by higher order LR clustering. Using a panel of deletion mutants we were able to define a role for the CRH1 and Ig-like domains in leptin signaling. Moreover, we demonstrate a non-redundant function for the individual receptor chains within the homomeric LR complex. Based on these data, we propose a possible model for LR clustering.
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