sFRP1 Potentiation vs. Inhibition of Wnt3a/β-catenin Signaling: Mechanistic and Structure-Function Analysis

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	SIG-6

Authors

• C.P Xavier
• M Melikova
• S Saffo
• J.S Rubin

Abstract

Wnt signaling regulates a variety of cellular processes including proliferation, motility and polarity. Many of these activities are mediated by the Frizzled (Fzd) family of seven-pass transmembrane receptors, which bind Wnts via a conserved cyteine-rich domain (CRD). Secreted Fzd-related proteins (sFRPs) contain an amino-terminal, Fzd-like CRD and a carboxyl-terminal, heparin-binding netrin-like domain (NTR). Previous studies identified sFRPs as soluble Wnt antagonists that bind directly to Wnts and prevent their interaction with Fzds. However, subsequent observations suggested that sFRPs and Fzds can form homodimers and heterodimers via their respective CRDs, and that sFRPs may stimulate signal transduction. Here, we present evidence that sFRP1 either inhibits or potentiates the Wnt3a/β-catenin pathway, depending on its concentration and the cellular context. sFRP1 has biphasic activity in a SuperTopFlash (STF) reporter assay in HEK293/STF cells. The potentiating effect in HEK293/STF cells was mimicked by CRDsFRP-1, while CRDsFRP-1 did not inhibit Wnt3a activity even at micromolar concentrations. In contrast, sFRP1 only inhibited Wnt3a/β-catenin signaling in L929 fibroblasts. Interestingly, when L cells were engineered to stably express Fzd5 but not Fzd2 or Fzd4, sFRP1 enhanced Wnt3a/β-catenin signaling at nanomolar concentrations. Future experiments will explore the molecular mechanisms responsible for potentiation vs. inhibition of Wnt/β-catenin signaling by sFRP1.

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