Editors' ChoicePlanar Cell Polarity

Abl to Regulate PCP

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Science Signaling  12 Oct 2010:
Vol. 3, Issue 143, pp. ec313
DOI: 10.1126/scisignal.3143ec313

Polarization of cells within the plane of an epithelium depends upon planar cell polarity (PCP) signaling pathways, one of which is the Frizzled (Fz) PCP pathway. This pathway shares components with the canonical Wnt signaling pathway, specifically the seven-pass transmembrane protein Fz and the multidomain protein Dishevelled (Dsh). Singh et al. identified a member of the Abelson (Abl) family of tyrosine kinases, dAbl, as a regulator of Dsh in PCP signaling in the fruit fly. Flies homozygous for loss-of-function alleles of dAbl displayed phenotypes consistent with PCP defects, and removing dAbl function in developing photoreceptors or wing discs by RNA interference caused PCP defects in these tissues. Heterozygosity for dAbl suppressed PCP phenotypes caused by overexpression of Fz or Dsh in photoreceptors but did not repress PCP phenotypes caused by overexpression of PCP components downstream of Dsh or the Dsh downstream effector Rac1. Misexpression experiments in the wing disc indicated that dAbl was not required for canonical Wnt signaling. Dsh and dAbl physically interacted in immunoprecipitation assays using extracts from insect S2 cells or human 293T cells that expressed epitope-tagged versions of both proteins. Glutathione S-transferase (GST) pull-down assays with purified proteins identified the proline-rich region downstream of the PDZ domain of Dsh as the site of interaction with dAbl, and purified Abl phosphorylated both Dsh and the mouse homolog Dvl1 in the DEP (disheveled, Egl-10, pleckstrin) domain, which is required for membrane localization of Dsh and may mediate activation of downstream effectors. Mutation of Tyr473 to Phe in the DEP domain reduced in vitro phosphorylation of Dsh by Abl; in vivo, this mutation abolished Dsh activity in PCP signaling and reduced Dsh membrane localization but did not affect its ability to transduce canonical Wnt signaling. The authors also demonstrated that mouse embryonic fibroblasts lacking both Abl1 and Abl2 showed decreased phosphorylation of Dvl2 and Dvl3 accompanied by failure of Dvl2 to localize to the membrane, yet had no defects in canonical Wnt signaling. Together these findings indicate that Abelson kinases, in addition to functioning in cell junctions and apical constriction, also play a conserved role in PCP signaling during development. Importantly, the involvement of Abl sheds light on pathway-specific Dsh regulation.

J. Singh, W. A. Yanfeng, L. Grumolato, S. A. Aaronson, M. Mlodzik, Abelson family kinases regulate Frizzled planar cell polarity signaling via Dsh phosphorylation. Genes Dev. 24, 2157–2168 (2010). [Abstract] [Full Text]