Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity

Speck, Olga; Hughes, Sarah C.; Noren, Nicole K.; Kulikauskas, Rima M.; Fehon, Richard G.

doi:10.1038/nature01295

Cited by 243 publications

(283 citation statements)

References 30 publications

Supporting

Mentioning

256

Contrasting

Unclassified

Order By: Relevance

“…In epithelial cells, an active form of ezrin has been shown to activate the small GTPase Rac1 with a concomitant disassembly of adherens junctions (Pujuguet et al, 2003). A genetic analysis in Drosophila, however, has suggested that Drosophila moesin negatively regulates the Rho1 pathway (Speck et al, 2003). Therefore, these data reveal a complex relationship between ERM proteins and the small GTPases, supporting the idea that ERM proteins function both upstream and downstream of Rho GTPases.…”

supporting

confidence: 57%

Interaction of Ezrin with the Novel Guanine Nucleotide Exchange Factor PLEKHG6 Promotes RhoG-dependent Apical Cytoskeleton Rearrangements in Epithelial Cells

D'Angelo

Aresta

Blangy

et al. 2007

MBoC

View full text Add to dashboard Cite

The mechanisms underlying functional interactions between ERM (ezrin, radixin, moesin) proteins and Rho GTPases are not well understood. Here we characterized the interaction between ezrin and a novel Rho guanine nucleotide exchange factor, PLEKHG6. We show that ezrin recruits PLEKHG6 to the apical pole of epithelial cells where PLEKHG6 induces the formation of microvilli and membrane ruffles. These morphological changes are inhibited by dominant negative forms of RhoG. Indeed, we found that PLEKHG6 activates RhoG and to a much lesser extent Rac1. In addition we show that ezrin forms a complex with PLEKHG6 and RhoG. Furthermore, we detected a ternary complex between ezrin, PLEKHG6, and the RhoG effector ELMO. We demonstrate that PLEKHG6 and ezrin are both required in macropinocytosis. After down-regulation of either PLEKHG6 or ezrin expression, we observed an inhibition of dextran uptake in EGF-stimulated A431 cells. Altogether, our data indicate that ezrin allows the local activation of RhoG at the apical pole of epithelial cells by recruiting upstream and downstream regulators of RhoG and that both PLEKHG6 and ezrin are required for efficient macropinocytosis. INTRODUCTIONThe membrane-cytoskeleton linker ezrin is mainly expressed in epithelial cells where it associates to the apical actin-rich structures such as microvilli (Berryman et al., 1993(Berryman et al., , 1995. Recent genetic analyses revealed that ezrin is essential for the morphogenesis of epithelial cells (Fiévet et al., 2007). In ezrin Ϫ/Ϫ mice, morphological defects in the apical domain of intestinal and retinal pigment epithelial cells have been observed (Saotome et al., 2004;Bonilha et al., 2006). In parietal cells, ezrin knockdown impairs the formation of canalicular apical membrane, resulting in severe achlorhydria (Tamura et al., 2005).How ezrin participates in the assembly of the apical actinrich structures such as microvilli is still poorly understood. The association of ezrin and the highly related proteins radixin and moesin with the cortical actin cytoskeleton is strictly regulated. ERM (ezrin, radixin, moesin) proteins contain a conserved globular N-terminal domain, called the FERM domain (Four point one ezrin, radixin, moesin), involved in the binding to both phosphatidylinositol 4,5 bisphosphate (PIP 2 ; Barret et al., 2000) and plasma membrane proteins and a C-terminal F-actin-binding domain that resides in the last 34 amino acids (Turunen et al., 1994;Bretscher et al., 2002). In the cytoplasm, ERM proteins exist in a closed conformation because of an intramolecular interaction between the N-terminal domain and the last 100 amino acids called N-and C-ERMAD (ERM association domain), respectively . This intramolecular association masks the binding sites for plasma membrane proteins and F-actin. An activation step is required to disrupt this association that occurs through conformational changes induced by sequential binding to PIP 2 and phosphorylation of a conserved C-terminal threonine residue (T567 in ezrin; Matsui et al., 1998;Fié...

show abstract

supporting

confidence: 57%

Interaction of Ezrin with the Novel Guanine Nucleotide Exchange Factor PLEKHG6 Promotes RhoG-dependent Apical Cytoskeleton Rearrangements in Epithelial Cells

D'Angelo

Aresta

Blangy

et al. 2007

MBoC

View full text Add to dashboard Cite

show abstract

“…MLF1IP shows 25% identity to the SMC family of proteins (Schmiesing et al, 1998;Gregson et al, 2001), and some homology to myosin (Cope et al, 1996), moesin, which is involved in actin cytoskeletal organization (Speck et al, 2003), and to a lesser extent to vacuolar ATPase subunit a, which targets this proton pump to various cellular locations (Kawasaki-Nishi et al, 2001). SMC and myosin families are ATP-driven molecular motors involved in a number of cellular events such as movement, translocation, cell division and maintenance of cellular structures.…”

Section: Discussionmentioning

confidence: 99%

cDNA cloning and characterization of a novel gene encoding the MLF1-interacting protein MLF1IP

et al. 2004

View full text Add to dashboard Cite

Myelodysplasia/acute myeloid leukemia (MDS/AML) is characterized by a t(3;5)(q25.1;q34) chromosomal translocation that forms a fusion gene between nucleophosmin (NPM) and MDS/myeloid leukemia factor 1 (MLF1). We identified a novel protein, MLF1-interacting protein (MLF1IP), that specifically associates with MLF1 by yeast two-hybrid analysis and in pulldown assays, and colocalizes with it in both the nuclei and cytoplasm of cells. The MLF1IP gene locus is at chromosome 4q35.1 and is composed of 14 exons spanning 75.8 kb of genomic DNA. The MLF1IP cDNA encodes a 46-kDa protein that contains two bipartite and two classical nuclear localization signals, two nuclear receptor-binding motifs (LXXLL), two leucine zippers, two PEST residues and several potential phosphorylation sites. MLF1IP transcripts are expressed in a variety of tissues (e.g. fetal liver, bone marrow, thymus and testis). MLF1IP appears to be a lineage-specific gene whose expression is confined exclusively to the CFU-E erythroid precursor cells, but not in mature erythrocytes. These observations, together with previous data demonstrating a role for MLF1 in suppressing red cell maturation, suggest a possible role for MLF1IP and MLF1 deregulation in the genesis of erythroleukemias.

show abstract

“…In Drosophila, the latter step is mediated by the sterile 20 family kinase Slik (Hipfner et al, 2004). It has been proposed that activated Drosophila moesin influences the organization of the cortical cytoskeleton by acting antagonistically to the Rho signalling pathway (Speck et al, 2003;Xu et al, 2011). Notably, Slik and Rho signalling components seem to be expressed at a high level in the adult Drosophila salivary gland (Chintapalli et al, 2007).…”

Section: Morphogenesis Of the Secretory Cellsmentioning

confidence: 99%

Development of apical membrane organization and V-ATPase regulation in blowfly salivary glands

Baumann

Bauer

2013

Journal of Experimental Biology

View full text Add to dashboard Cite

show abstract

Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity

Cited by 243 publications

References 30 publications

Interaction of Ezrin with the Novel Guanine Nucleotide Exchange Factor PLEKHG6 Promotes RhoG-dependent Apical Cytoskeleton Rearrangements in Epithelial Cells

Interaction of Ezrin with the Novel Guanine Nucleotide Exchange Factor PLEKHG6 Promotes RhoG-dependent Apical Cytoskeleton Rearrangements in Epithelial Cells

cDNA cloning and characterization of a novel gene encoding the MLF1-interacting protein MLF1IP

Development of apical membrane organization and V-ATPase regulation in blowfly salivary glands

Contact Info

Product

Resources

About