Research Article: Subcellular Localization of Frizzled Receptors, Mediated by Their Cytoplasmic Tails, Regulates Signaling Pathway Specificity

Date Published: July 13, 2004

Publisher: Public Library of Science

Author(s): Jun Wu, Thomas J Klein, Marek Mlodzik

Abstract: The Frizzled (Fz; called here Fz1) and Fz2 receptors have distinct signaling specificities activating either the canonical Wnt/β-catenin pathway or Fz/planar cell polarity (PCP) signaling in Drosophila. The regulation of signaling specificity remains largely obscure. We show that Fz1 and Fz2 have different subcellular localizations in imaginal disc epithelia, with Fz1 localizing preferentially to apical junctional complexes, and Fz2 being evenly distributed basolaterally. The subcellular localization difference directly contributes to the signaling specificity outcome. Whereas apical localization favors Fz/PCP signaling, it interferes with canonical Wnt/β-catenin signaling. Receptor localization is mediated by sequences in the cytoplasmic tail of Fz2 that appear to block apical accumulation. Based on these data, we propose that subcellular Fz localization, through the association with other membrane proteins, is a critical aspect in regulating the signaling specificity within the Wnt/Fz signaling pathways.

Partial Text: Pattern formation in multicellular organisms relies on inductive signaling events. Several evolutionarily conserved ligand–receptor combinations and associated signal transduction pathways are used again and again during development to induce tissue- and cell-type-specific responses. Thus, context-dependent signaling specificity is an important prerequisite for patterning and differentiation. Although for many signaling pathways the flow of information is largely established, the underlying signaling specificity mechanisms remain unclear.

We have shown that Fz1 and Fz2 have different subcellular localizations within the wing imaginal epithelium. This difference is mediated by sequences in the cytoplasmic tail of Fz2 that appear to block apical accumulation. The subcellular localization difference directly contributes to the signaling specificity outcome. Whereas apical localization favors Fz/PCP signaling, it interferes with canonical Wnt/β-cat signaling.

Source:

http://doi.org/10.1371/journal.pbio.0020158

 

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