Editors' ChoiceDevelopmental Biology

Separating Fat Functions

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Science Signaling  05 Feb 2013:
Vol. 6, Issue 261, pp. ec32
DOI: 10.1126/scisignal.2004031

Fat is an atypical cadherin that participates in both the Hippo growth control pathway and the planar cell polarity (PCP) pathway. Studies in flies indicated that many inputs can activate Hippo signaling at the level of the kinase Warts (Wts), which phosphorylates the transcription factor Yorkie to exclude it from the nucleus. Fat impinges on Hippo signaling through modulation of the distribution of Dachs, a myosin that represses Wts activity. Signaling through the PCP pathway is activated when Fat molecules on one cell bind to the atypical cadherin Dachsous (Ds) from a neighboring cell. Fat is uniformly distributed across the tissue, but Ds is distributed in a gradient across the tissue. Polarized activation of Fat is required for the proper membrane localization and polarization of Dachs. It has been proposed that the effects of Dachs and Fat on Hippo signaling are determined by the amount of these proteins present at the membrane, whereas their effects on PCP signaling are determined by the direction in which their distribution is polarized. Pan et al. have identified distinct regions of the intracellular domain of Fat that are specifically involved in Hippo and PCP signaling. Mutant forms of Fat lacking various regions of the intracellular domain were tested for their ability to rescue growth (Hippo) and patterning (PCP) defects in Drosophila melanogaster fat mutant wing discs. Inhibiting Hippo signaling in wing discs produces wings that are larger than wild-type wings, whereas inhibiting PCP signaling produces wings that are less elongated than wild-type and show disrupted wing hair polarization. The four C-terminal amino acids of Fat were required for optimal Fat-PCP signaling but dispensable for Fat-Hippo signaling. This motif is conserved in mouse Fat4, which contributes to PCP, but not Hippo, signaling. A separate motif in the central portion of the intracellular domain was required for Fat-Hippo signaling but had little effect on Fat-PCP signaling. This domain overlapped with a potential site for phosphorylation by Discs overgrown (Dco), the Drosophila homolog of casein kinase 1ε, which is required for Fat-Hippo signaling. Although precise details of the mechanisms differentiating Fat activity in the Hippo and PCP signaling pathways remain unclear, Fat activity in the two pathways relies on molecular differences in signal transduction, not just on its abundance or distribution.

G. Pan, Y. Feng, A. A. Ambegaonkar, G. Sun, M. Huff, C. Rauskolb, K. D. Irvine, Signal transduction by the Fat cytoplasmic domain. Development 140, 831–842 (2013). [Abstract] [Full Text]