Protéines LAP : de nouvelles clés de voûte de l’architecture épithéliale

La polarité, une des propriétés les plus importantes des épithéliums, se manifeste par la formation de deux domaines membranaires distincts, apical et basolatéral, dont les fonctions sont spécialisées. La formation, le maintien et les fonctions des tissus épithéliaux sont assurés par un canevas de protéines de surface connectées à des réseaux intracellulaires de molécules de structure et de signalisation organisant la polarité spécialisée du tissu, et contrôlant ses relations avec le milieu extérieur. Au sein de ces échafaudages moléculaires, les protéines à domaines PDZ (PSD95/Dlg/ZO-1) tiennent une place prépondérante en assurant l’assemblage et la distribution subcellulaire des acteurs de l’homéostasie épithéliale. Parmi celles-ci, les protéines de la famille LAP (LRR and PDZ) occupent le devant de la scène en raison de leur implication dans les étapes-clés de la différenciation épithéliale. De plus, l’étude de modèles génétiques invertébrés et vertébrés a notamment permis de mettre en exergue leur rôle central au cours du développement embryonnaire et de dévoiler, pour certaines protéines LAP, un rôle potentiel de suppresseur de tumeur.Cell proliferation and cell differentiation are balanced processes required for the correct development and maintenance of tissues, including epithelial tissues. Disruption of this balance by downregulation or loss of function of gatekeepers of epithelial homeostasis may unleash tumor suppressing activities leading ultimately to tumorigenesis. Among the newcoming actors involved in epithelial cell polarity, recent data shed light on the crucial role played by the LAP (LRR And PDZ) protein family. LAP proteins assemble receptors, cytoplasmic adaptors and enzymes in multimolecular networks important for the different steps of epithelial differentiation : adhesion, building of tight junctions and trafficking of proteins along the secretory pathway. Furthermore, genetic studies in invertebrates and vertebrates have installed LAP proteins not only as crucial determinants for epithelial integrity but also as key regulators of cell proliferation and embryonic development

Basolateral targeting by leucine‐rich repeat domains in epithelial cells

The asymmetric distribution of proteins to basolateral and apical membranes is an important feature of epithelial cell polarity. To investigate how basolateral LAP proteins (LRR (for leucine-rich repeats) and PDZ (for PSD-95/Discs-large/ZO-1), which play key roles in cell polarity, reach their target membrane, we carried out a structure–function study of three LAP proteins: Caenorhabditis elegans LET-413, human Erbin and human Scribble (hScrib). Deletion and point mutation analyses establish that their LRR domain is crucial for basolateral membrane targeting. This property is specific to the LRR domain of LAP proteins, as the non-LAP protein SUR-8 does not localize at the basolateral membrane of epithelial cells, despite having a closely related LRR domain. Importantly, functional studies of LET-413 in C. elegans show that although its PDZ domain is dispensable during embryogenesis, its LRR domain is essential. Our data establish a novel paradigm for protein localization by showing that a subset of LRR domains direct subcellular localization in polarized cells

Etude de l'implication d'Erbin, une protéine de la famille LAP, dans l'établissement de la polarité épithéliale

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

ERBIN: a basolateral PDZ protein that interacts with the mammalian ERBB2/HER2 receptor

The ERBB receptors have a crucial role in morphogenesis and oncogenesis. We have identified a new PDZ protein we named ERBIN (ERBB2 interacting protein) that acts as an adaptor for the receptor ERBB2/HER2 in epithelia. ERBIN contains 16 leucine-rich repeats (LRRs) in its amino terminus and a PDZ (PSD-95/DLG/ZO-1) domain at its carboxy terminus, and belongs to a new PDZ protein family. The PDZ domain directly and specifically interacts with ERBB2/HER2. ERBIN and ERBB2/HER2 colocalize to the lateral membrane of human intestinal epithelial cells. The ERBIN-binding site in ERBB2/HER2 has a critical role in restricting this receptor to the basolateral membrane of epithelial cells, as mutation of the ERBIN-binding site leads to the mislocalization of the receptor in these cells. We suggest that ERBIN acts in the localization and signalling of ERBB2/HER2 in epithelia