A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors

A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors

^*Department of Molecular Biology and Genetics, ^§Department of Neuroscience, ^¶Department of Ophthalmology, and ^†Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and ^‡Mammalian Genetics Laboratory, Advanced BioScience Laboratory Basic Research Program, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, MD 21702

Abstract

This paper describes the identification of a new family of mammalian genes that encode secreted proteins containing homology to the cysteine-rich ligand-binding domain found in the frizzled family of transmembrane receptors. The secreted frizzled-related proteins (sFRPs) are approximately 30 kDa in size, and each contains a putative signal sequence, a frizzled-like cysteine-rich domain, and a conserved hydrophilic carboxy-terminal domain. The sFRPs are not the products of differential splicing of the known frizzled genes. Glycosylphosphatidylinositol-anchored derivatives of sFRP-2 and sFRP-3 produced in transfected human embryonic kidney cells confer cell-surface binding by the Drosophila Wingless protein. These observations suggest that sFRPs may function in vivo to modulate Wnt signaling, or, alternatively, as novel ligands for as yet unidentified receptors.

Footnotes

↵ ‖ To whom reprint requests should be addressed at: 805 Preclinical Teaching Building, 725 North Wolfe Street, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Jeremy Nathans
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. U88566–U88569U88566 U88567 U88568 U88569).
ABBREVIATIONS:

CRD,

cysteine-rich domain;

DAF,

decay activating factor;

EST,

expressed sequence tag;

GPI,

glycosylphosphatidylinositol;

RFLPs,

restriction fragment length polymorphisms;

sFRP,

secreted frizzled-related protein