CRB3

Last update 08 May 2025

Basic Info

Synonyms

CRB3, crumbs cell polarity complex component 3, MGC17303

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Introduction

Involved in the establishment of cell polarity in mammalian epithelial cells (PubMed:12771187, PubMed:14718572, PubMed:23439680). Regulates the morphogenesis of tight junctions (PubMed:12771187, PubMed:14718572). Involved in promoting phosphorylation and cytoplasmic retention of transcriptional coactivators YAP1 and WWTR1/TAZ which leads to suppression of TGFB1-dependent transcription of target genes such as CCN2/CTGF, SERPINE1/PAI1, SNAI1/SNAIL1 and SMAD7 (By similarity).

100 Clinical Results associated with CRB3

100 Translational Medicine associated with CRB3

0 Patents (Medical) associated with CRB3

118

Literatures (Medical) associated with CRB3

01 Oct 2024·Nature Cell Biology

A size filter at the Golgi regulates apical membrane protein sorting

Article

Author: de Caestecker, Christian ; Macara, Ian G. ; Macara, Ian G

Despite decades of research, apical sorting of epithelial membrane proteins remains incompletely understood. We noted that apical cytoplasmic domains are smaller than those of basolateral proteins; however, the reason for this discrepancy is unknown. Here we used a synthetic biology approach to investigate whether a size barrier at the Golgi apparatus might hinder apical sorting of proteins with large cytoplasmic tails. We focused on Crb3, Ace2 and Muc1 as representative apical proteins with short cytoplasmic tails. By incorporating a streptavidin-binding peptide, these proteins can be trapped in the endoplasmic reticulum until addition of biotin, which triggers synchronous release to the Golgi and subsequent transport to the apical cortex. Strikingly, increasing the size of their cytoplasmic domains caused partial mislocalization to the basolateral cortex and significantly delayed Golgi departure. Moreover, N-glycosylation of 'large' Crb3 was delayed, and 'small' Crb3 segregated into spatially distinct Golgi regions. Biologically, Crb3 forms a complex through its cytoplasmic tail with the Pals1 protein, which could also delay departure, but although associated at the endoplasmic reticulum and Golgi, Pals1 disassociated before Crb3 departure. Notably, a non-dissociable mutant Pals1 hampered the exit of Crb3. We conclude that, unexpectedly, a size filter at the Golgi facilitates apical sorting of proteins with small cytoplasmic domains and that timely release of Pals1, to reduce cytoplasmic domain size, is essential for normal Crb3 sorting.

01 Jun 2024·Life Science Alliance

Human CRB1 and CRB2 form homo- and heteromeric protein complexes in the retina

Article

Author: Boldt, Karsten ; Stehle, Isabel F ; Woerz, Franziska ; Hoffmann, Felix ; Ueffing, Marius ; Imventarza, Joel A ; Beyer, Tina ; Quinn, Peter MJ

Crumbs homolog 1(CRB1) is one of the key genes linked to retinitis pigmentosa and Leber congenital amaurosis, which are characterized by a high clinical heterogeneity. The Crumbs family member CRB2 has a similar protein structure to CRB1, and in zebrafish, Crb2 has been shown to interact through the extracellular domain. Here, we show that CRB1 and CRB2 co-localize in the human retina and human iPSC-derived retinal organoids. In retina-specific pull-downs, CRB1 was enriched in CRB2 samples, supporting a CRB1–CRB2 interaction. Furthermore, novel interactors of the crumbs complex were identified, representing a retina-derived protein interaction network. Using co-immunoprecipitation, we further demonstrate that human canonical CRB1 interacts with CRB1 and CRB2, but not with CRB3, which lacks an extracellular domain. Next, we explored how missense mutations in the extracellular domain affect CRB1–CRB2 interactions. We observed no or a mild loss of CRB1–CRB2 interaction, when interrogating various CRB1 or CRB2 missense mutants in vitro. Taken together, our results show a stable interaction of human canonical CRB2 and CRB1 in the retina.

01 Mar 2024·Journal of Cell Science

PALS1 is a key regulator of the lateral distribution of tight junction proteins in renal epithelial cells

Article

Author: Möller-Kerutt, Annika ; Kleimann, Simon ; Nedvetsky, Pavel ; Gilhaus, Kevin ; Ludwig, Alexander ; Weide, Thomas ; Ebnet, Klaus ; Höffken, Verena ; Ghosh, Sujasha ; Pavenstädt, Hermann ; Groh, Ann-Christin ; Hansen, Uwe ; Krahn, Michael P ; Behrens, Malina

ABSTRACTThe evolutionarily conserved apical Crumbs (CRB) complex, consisting of the core components CRB3a (an isoform of CRB3), PALS1 and PATJ, plays a key role in epithelial cell–cell contact formation and cell polarization. Recently, we observed that deletion of one Pals1 allele in mice results in functional haploinsufficiency characterized by renal cysts. Here, to address the role of PALS1 at the cellular level, we generated CRISPR/Cas9-mediated PALS1-knockout MDCKII cell lines. The loss of PALS1 resulted in increased paracellular permeability, indicating an epithelial barrier defect. This defect was associated with a redistribution of several tight junction-associated proteins from bicellular to tricellular contacts. PALS1-dependent localization of tight junction proteins at bicellular junctions required its interaction with PATJ. Importantly, reestablishment of the tight junction belt upon transient F-actin depolymerization or upon Ca2+ removal was strongly delayed in PALS1-deficient cells. Additionally, the cytoskeleton regulator RhoA was redistributed from junctions into the cytosol under PALS1 knockout. Together, our data uncover a critical role of PALS1 in the coupling of tight junction proteins to the F-actin cytoskeleton, which ensures their correct distribution along bicellular junctions and the formation of tight epithelial barrier.

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