Signal transduction by the Fat cytoplasmic domain

Abstract

SUMMARYThe large atypical cadherin Fat is a receptor for both Hippo and planar cell polarity (PCP) pathways. Here we investigate the molecular basis for signal transduction downstream of Fat by creating targeted alterations within a genomic construct that contains the entire fat locus, and by monitoring and manipulating the membrane localization of the Fat pathway component Dachs. We establish that the human Fat homolog FAT4 lacks the ability to transduce Hippo signaling in Drosophila, but can transduce Drosophila PCP signaling. Targeted deletion of conserved motifs identifies a four amino acid C-terminal motif that is essential for aspects of Fat-mediated PCP, and other internal motifs that contribute to Fat-Hippo signaling. Fat-Hippo signaling requires the Drosophila Casein kinase 1ε encoded by discs overgrown (Dco), and we characterize candidate Dco phosphorylation sites in the Fat intracellular domain (ICD), the mutation of which impairs Fat-Hippo signaling. Through characterization of Dachs localization and directed membrane targeting of Dachs, we show that localization of Dachs influences both the Hippo and PCP pathways. Our results identify a conservation of Fat-PCP signaling mechanisms, establish distinct functions for different regions of the Fat ICD, support the correlation of Fat ICD phosphorylation with Fat-Hippo signaling, and confirm the importance of Dachs membrane localization to downstream signaling pathways.

Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development

“…Embryos mutant for Fat4 exhibit PCP defects, suggesting that the polarity function of Fat is conserved (Saburi et al, 2008;Mao et al, 2011). The Fat4 intracellular domain can rescue most of the PCP defects of fat mutant flies (Pan et al, 2013). Although structure/function analyses suggest that the Drosophila growth regulatory domain is not conserved in Fat4 (Matakatsu and Blair, 2012;Zhao et al, 2013;Bossuyt et al, 2014), Fat4 restricts the growth of neuronal progenitors in the developing chick neural tube (Van Hateren et al, 2011).…”

Transcriptional analysis of the dachsous gene uncovers novel isoforms expressed during development in Drosophila

“…The average for distance and area was normalized to control females. Measurement of the A-PCV distance was carried out as described in [11]. The wing area parameter was calculated by dividing the posterior area (P) by the total area (T) (Fig.…”

“…Significant progress has been made in understanding the mechanism by which Ft regulates PCP and growth, due to the identification of cytoplasmic partners that interact with specific sequence motifs of Ft cytoplasmic domain (CD) [10][11][12][13]. However, the molecular mechanism of Ds regulating PCP and the Hippo pathway is less well understood.…”

Regulation of long-range planar cell polarity by Fat-Dachsous signaling

“…Recent studies (Bossuyt et al, 2013;Matakatsu and Blair, 2012;Pan et al, 2013;Zhao et al, 2013) have conducted extensive structure-function analyses of Ft to identify regions important for Ft activity in different pathways ( Figure 6). Matakatsu and Blair (Matakatsu and Blair, 2012) searched for the minimal regions required to rescue abdominal polarity and wing disc growth phenotypes of ft.…”

“…Similarly, many known interactor binding sites are dispensable for regulation of polarity by Ft in the eye (Zhao et al, 2013 In summation, both ECDs and ICDs of Ft and Ds have context-dependent roles in regulating polarity and growth control ( Figure 6 and Table 2). Matakatsu and Blair, 2012;Zhao et al, 2013;Bossuyt et al, 2013;Sopko et al, 2009;Pan et al, 2013;Fanto et al, 2003;Mao et al, 2009. (Ma et al, 2003).…”