sFRPs

Secreted frizzled-related proteins (sFRPs) are a family of secreted glycoproteins that modulate Wnt signaling. In humans the family comprises five members: SFRP1, SFRP2, SFRP3 (also known as FRZB), SFRP4, and SFRP5. They share an N-terminal cysteine-rich domain homologous to the extracellular region of Frizzled receptors and a more divergent C-terminal domain; unlike Frizzled receptors, sFRPs lack transmembrane and intracellular signaling regions, placing them in the extracellular modulators of Wnt signaling.

Mechanism and function: sFRPs commonly bind Wnt ligands through their CRD, sequestering these ligands away from Frizzled receptors and thereby inhibiting canonical (β-catenin–dependent) Wnt signaling. They can also influence noncanonical Wnt pathways and, in some contexts, exert Wnt-independent effects by interacting with other extracellular components. The overall outcome is highly context-dependent, varying with tissue type, developmental stage, and the repertoire of Wnt ligands and Frizzled receptors present.

Expression and regulation: sFRPs are broadly expressed during development and in adult tissues. In cancer, several SFRP genes are frequently silenced by promoter hypermethylation, reducing Wnt inhibition and often contributing to tumorigenic signaling; however, paradoxical pro-tumor effects mediated by non-Wnt pathways have been reported in certain contexts.

Clinical relevance: Because of their role in modulating Wnt signaling, sFRPs have been explored as biomarkers and therapeutic targets. Methylation status of SFRP genes can serve as diagnostic or prognostic indicators in colorectal, breast, and other cancers. Therapeutic strategies include restoring sFRP function or mimicking their Wnt-inhibitory activity, though clinical translation is complicated by context-dependent effects.

History: The sFRP family was identified in the late 1990s as secreted frizzled-related proteins associated with Wnt signaling.