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Tissue restricted expression of two human Frzbs in preadipocytes and pancreas
1Department of Renal Pharmacology, Department of Bio-Pharmacology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania, 19406, USA.
Abstract:
Frzb is a newly discovered family of secreted glycoproteins that function to modulate signaling activity of Wnt. Frzb proteins share sequence homology with the extracellular domain of the Wnt receptor (frizzled) and are capable of binding to Wnt. Thus, Frzb functions to antagonize Wnt activity by sequestering Wnt and preventing its binding to the frizzled 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 expression 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 experiments revealed that these Frzb homologues have highly restricted tissue distribution. hFRP-1b is exclusively expressed in pancreatic tissue while 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-2 is also significantly reduced in fat pads from obese mice. Taken together, these data indicate that distinctive members of the Frzb family exhibit different expression patterns in vivo, suggesting their ability to modulate diverse aspects of Wnt signaling. The expression and dysregulation of sFRP-2 in fat and obesity also suggest a potential 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-Frzb interaction and their impact on Wnt-Frizzled receptor signal transduction.
Insights
Frzb proteins antagonize Wnt signaling by binding Wnt. Two human homologues, hFRP-1b and hFRP-2, show restricted tissue expression, with FRP-2 linked to obesity and metabolic diseases.
Area of Science:
- Molecular Biology
- Biochemistry
- Endocrinology
Background:
- Frzb (Frizzled-related proteins) are secreted glycoproteins modulating Wnt signaling.
- They bind Wnt, acting as antagonists by preventing receptor interaction.
- Previous studies identified bovine and human Frzb, with related members found in rodents and humans.
Purpose of the Study:
- To clone and characterize two novel human Frzb homologues, hFRP-1b and hFRP-2.
- To investigate the tissue distribution and expression patterns of these human Frzb homologues.
- To explore the potential role of Frzb family members, particularly FRP-2, in obesity and metabolic diseases.
Main Methods:
- Molecular cloning of human Frzb homologues hFRP-1b and hFRP-2.
- Expression analysis using Northern blot to determine tissue distribution.
- Comparison of amino acid identity with known mouse homologues (sFRP-1 and sFRP-2).
Main Results:
- hFRP-1b and hFRP-2 share significant homology with mouse sFRP-1 and sFRP-2.
- hFRP-1b is exclusively expressed in pancreatic tissue.
- hFRP-2 is highly expressed in adipose tissue, particularly in undifferentiated preadipocytes, and its expression is reduced in obese mice.
Conclusions:
- Distinct Frzb family members exhibit unique in vivo expression patterns, suggesting diverse roles in Wnt signaling modulation.
- The expression and dysregulation of sFRP-2 in adipose tissue indicate a potential role in the Wnt pathway's involvement in obesity and metabolic disorders.
- Cloning and expression of these Frzbs facilitate further studies on Wnt-Frzb interactions and their impact on Wnt-Frizzled receptor signaling.