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J. Biol. Chem., Vol. 278, Issue 35, 33232-33238, August 29, 2003

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A Novel Interleukin-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, László G. Kömüves, Mary E. Gerritsen and James N. Topper

From the Department of Cardiovascular Research, Millennium Pharmaceuticals, Inc., South San Francisco, California 94080

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. 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 (IL-17) receptor family. Real-time quantitative PCR and Northern analyses revealed that this gene is highly expressed in human umbilical vein endothelial cells 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 human SEF (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-17 receptor-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.

Received for publication, May 13, 2003 , and in revised form, June 6, 2003.

^* This work was supported by a NHLBI, National Institutes of Health Award HL-62823 (to J. N. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Cardiovascular Research, Millennium Pharmaceuticals, Inc., 256 E. Grand Ave., South San Francisco, CA 94080. Tel.: 650-246-7344; Fax: 650-244-9270; E-mail: rueybing{at}yahoo.com. Present address: Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Sec. 2, Taipei 115, Taiwan, Republic of China.

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