TISSUE RESTRICTED EXPRESSION OF 2 HUMAN FRZBS IN PREADIPOCYTES AND PANCREAS

Frzb is a newly discovered family of secreted glycoproteins that funct ion to modulate signaling activity of Wnt. Frzb proteins share sequenc e homology with the extracellular domain of the Wnt receptor (frizzled ) and are capable of binding to Wnt. Thus, Frzb functions to antagoniz e Wnt activity by sequestering Wnt and preventing its binding to the f rizzled receptor. Since the initial identification of bovine and human Frzb, several related members of this family have been isolated from rodent and human. In this paper, we describe the cloning and expressio n of two human frzb homologues termed hFRP-1b and hFRP-2. These human FRPs share significant homology to mouse sFRP-1 and sFRP-2 (55 and 98% identity at amino acid level, respectively). Northern blot experiment s revealed that these Frzb homologues have highly restricted tissue di stribution, hFRP-1b is exclusively expressed in pancreatic tissue whil e high levels of hFRP-2 were found in adipose tissue. In addition, low levels of hFRP-2 were also observed in other tissues including heart, pancreas and muscle. Remarkably, FRP-2 is predominantly expressed in un-differentiated preadipocytes in both rodent and man. The expression of FRP-S is also significantly reduced in fat pads from obese mice. T aken together, these data indicate that distinctive members of the Frz b family exhibit different expression patterns in vivo, suggesting the ir ability to modulate diverse aspects of Wnt signaling. The expressio n and dysregulation of sFRP-2 in fat and obesity also suggest a potent ial roles on the Wnt signaling pathway in the pathology of obesity and related metabolic diseases. Molecular cloning and expression of these Frzbs will allow detailed molecular and biochemical analysis of Wnt-F rzb interaction and their impact on Wnt-Frizzled receptor signal trans duction. (C) 1998 Academic Press.