Crumbs promotes expanded recognition and degradation by the SCF ^{Slimb/β-TrCP} ubiquitin ligase

Abstract

Significance Regulation of tissue growth is essential for metazoan development and adult homeostasis. The Hippo (Hpo) pathway is an evolutionarily conserved signaling cascade that has emerged as a crucial regulator of tissue size by virtue of its control of cell proliferation and cell death. Multiple epithelial architecture inputs converge on Hpo signaling, allowing tissues to quickly respond to disruptions in cell–cell and cell–matrix interactions. Here, we show that the polarity protein Crumbs promotes the apical localization and degradation of the Hpo pathway protein Expanded, by the SCF Slmb/β-TRCP ubiquitin ligase. This ubiquitin-dependent mechanism could potentially allow the dynamic regulation of Hpo signaling in response to changes in polarity.

Drosophila Crumbs prevents ectopic Notch activation in developing wings by inhibiting ligand-independent endocytosis

“…Although Crb is expressed in all cells of Drosophila imaginal discs, the anlagen of the external organs of the adult fly, epithelial integrity is not affected by the loss of crb function in these tissues (Hafezi et al, 2012;Herranz et al, 2006;Ribeiro et al, 2014). However, crb has been associated with various other functions in imaginal discs, such as regulation of Notch receptor processing in the wing margin (Herranz et al, 2006), cell survival (Hafezi et al, 2012) and organ size control by the Notch or Hippo pathways (Chen et al, 2010;Ling et al, 2010;Ribeiro et al, 2014;Richardson and Pichaud, 2010).…”

“…However, crb has been associated with various other functions in imaginal discs, such as regulation of Notch receptor processing in the wing margin (Herranz et al, 2006), cell survival (Hafezi et al, 2012) and organ size control by the Notch or Hippo pathways (Chen et al, 2010;Ling et al, 2010;Ribeiro et al, 2014;Richardson and Pichaud, 2010). In the pupal retinal epithelium, morphogenesis of photoreceptor cells is impaired upon loss of crb (Izaddoost et al, 2002;Johnson et al, 2002;Pellikka et al, 2002).…”

“…Results from structure-function analyses assigned specific functions to individual motifs within the short cytoplasmic tail. While the C-terminal PSD-95-Discs large-ZO-1 (PDZ) domain-binding motif of the cytoplasmic tail is essential for the regulation of polarity in embryonic epithelia (Klebes and Knust, 2000;Klose et al, 2013), its protein 4.1-ezrin-radixin-moesin (FERM) domain-binding motif participates in controlling dorsal closure during embryogenesis (Flores-Benitez and Knust, 2016;Klose et al, 2013) and Hippo-mediated growth of wing imaginal discs (Chen et al, 2010;Ling et al, 2010;Ribeiro et al, 2014). Less is known about the function of the huge extracellular domain.…”

“…The wing is an ideal system to study the genetic control of pattern formation and growth, and has been extensively used to unravel genetic interactions and epistatic relationships (reviewed in Blair, 2007;Ribeiro et al, 2014). We screened for mutations that dominantly modify the wing vein phenotype induced by overexpression of the membrane-bound extracellular domain of Crb.…”

Ebi modulates wing growth by ubiquitin-dependent downregulation of Crumbs in Drosophila

“…Crb has multiple functions, including roles in apicobasal cell polarity (Tepass et al, 1990;Wodarz et al, 1995;Tanentzapf et al, 2000), morphogenesis (Izaddoost et al, 2002;Pellikka et al, 2002), Hippo signaling (Parsons et al, 2010;Laprise, 2011;Ribeiro et al, 2014) and mitosis (Yeom et al, 2014). Interestingly, recent studies have provided evidence that Notch activity is affected by Crb.…”