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M305022200v1
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Papers In Press, published online ahead of print June 12, 2003
J. Biol. Chem, 10.1074/jbc.M305022200
Submitted on May 13, 2003
Revised on June 6, 2003
Accepted on June 12, 2003

A novel IL-17 receptor-like protein identified in human umbilical vein endothelial cells antagonizes basic fibroblast growth factor-induced signaling

Ruey-Bing Yang, Chi Kin Domingos Ng, Scott M. Wasserman, Laszlo G. Komuves, Mary E. Gerritsen, and James N. Topper

Vascular Biology, Millennium Pharmaceuticals, Inc., South San Francisco, CA 94080

Corresponding Author: rueybing{at}yahoo.com

We have previously utilized a combination of high-throughput sequencing and genome-wide microarray profiling analyses to identify novel cell-surface proteins expressed in human umbilical vein endothelial cells (HUVEC). One gene identified by this approach encodes a type I transmembrane receptor that shares sequence homology with the intracellular domain of members of the interleukin-17 receptor (IL-17R) family. Real-time quantitative PCR and Northern analyses revealed that this gene is highly expressed in HUVEC and in several highly vascularized tissues such as kidney, colon, skeletal muscle, heart and small intestine. In addition, we also found that it is also highly expressed in the ductal epithelial cells of human salivary glands, seminal vesicles and the collecting tubules of the kidney by in situ hybridization. This putative receptor, which we have termed hSEF, is also expressed in a variety of breast cancer tissues. In co-immunoprecipitation assays, this receptor is capable of forming homomeric complexes and can interact with fibroblast growth factor (FGF) receptor 1. Overexpression of this receptor inhibits FGF induction of an FGF-responsive reporter gene in human 293T cells. This appears to occur as a result of specific inhibition of p42/p44 ERK, in the absence of upstream MEK inhibition. This inhibitory effect is dependent upon a functional intracellular domain since deletion mutants missing the IL-17R-like domain lack this inhibitory effect. These findings are consistent with the recent discovery of the zebrafish homologue, Sef (similar expression to fgf genes), which specifically antagonizes FGF signaling when ectopically expressed in zebrafish or Xenopus laevis embryos. Based on sequence and functional similarities, this novel IL-17 receptor homologue represents a potential human SEF, and is likely to play critical roles in endothelial or epithelial functions such as proliferation, migration and angiogenesis.


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