The Crumbs3 Polarity Protein

Abstract

The Crumbs proteins are evolutionarily conserved apical transmembrane proteins. Drosophila Crumbs was discovered via its crucial role in epithelial polarity during fly embryogenesis. Crumbs proteins have variable extracellular domains but a highly conserved intracellular domain that can bind FERM and PDZ domain proteins. Mammals have three Crumbs genes and this review focuses on Crumbs3, the major Crumbs isoform expressed in mammalian epithelial cells. Although initial work has highlighted the role of Crumbs3 in polarity, more recent studies have found it has an important role in tissue morphogenesis functioning as a linker between the apical membrane and the actin cytoskeleton. In addition, recent publications have linked Crumbs3 to growth control via regulation of the Hippo/Yap pathway.

Figure 1.

Crumbs3 PDZ domain interactions. Through its carboxy-terminal tail (circle), Crumbs3 can bind two PDZ domain proteins, Pals1 (protein associated with lin-7 one) and Par6. Par6 can bind Par3 as well as atypical protein kinase C (aPKC), and aPKC can regulate basolateral polarity complexes via phosphorylation. Pals1 binds Patj (PALS1 associated tight junction protein) and Lin-7 via L27 domains. Patj has 10 PDZ domains that can mediate numerous interactions including to transmembrane tight junction proteins such as claudins and junctional adhesion molecules (JAMs), as well as to tight junction scaffolding proteins such as zonula occludens 3 (ZO-3).

Figure 2.

FERM-binding partners of Crumbs3. Through its FERM-binding domain (rectangle), Crumbs3 can connect to FERM domain-containing proteins. Crumbs3 can connect the apical membrane to the actin cytoskeleton and regulate the cell cortex via ezrin–radixin–moesin (ERM) proteins. Crumbs3 also binds Yurt family proteins, which negatively regulate Crumbs polarity signaling. Crumbs3 interacts with FERM domain proteins that regulate the Hippo/Yap pathway to control cell proliferation.