Disease relevance of Vil2

• Achlorhydria by ezrin knockdown: defects in the formation/expansion of apical canaliculi in gastric parietal cells [1].
• High ezrin expression in dog tumors was associated with early development of metastases [2].
• Consistent with this data, we found a significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients [2].
• Ezrin distribution is abnormal in principal cells from a murine model of autosomal recessive polycystic kidney disease [3].
• Together, these results suggest that blocking ezrin function may represent a novel and effective strategy for preventing breast cancer metastasis [4].

High impact information on Vil2

• From this genomic data, we selected ezrin for further study based on its role in physically and functionally connecting the actin cytoskeleton to the cell membrane [2].
• The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis [2].
• ICAM-2 redistributed by ezrin as a target for killer cells [5].
• Newly discovered cryptic actin-binding sites in vinculin and ezrin, two proteins recruited to adhesion sites, suggest that actin-binding proteins are targets for the signals generated by adhesion receptors [6].
• In vivo, blockade of ezrin leads to enhanced transplanted EC proliferation and angiogenesis in a mouse hind limb ischemia model [7].

Chemical compound and disease context of Vil2

• In embryonal carcinoma cells, both the abundance of ezrin and the proportion of ezrin associated with the cytoskeletal fraction increase upon induction of neuronal differentiation with retinoic acid [8].
• Another recurrent oncogenic form of tyrosine kinases (Flt3) most frequently involved in human myeloid leukemia was also able to phosphorylate ezrin [9].

Biological context of Vil2

• We then generated ezrin knockdown (Vil2(kd/kd)) mice by introducing a neomycin resistance cassette between exons 2 and 3 [1].
• No change in ezrin gene expression was found by RT-PCR [10].
• CONCLUSION: These changes in proximal Na/Pi cotransport may involve a signal transduction cascade including PDZ-dc1, ezrin, moesin, our phosphoprotein, and possibly other proteins [11].
• Normal development of mice and unimpaired cell adhesion/cell motility/actin-based cytoskeleton without compensatory up-regulation of ezrin or radixin in moesin gene knockout [12].
• The ezrin-like family of tyrosine kinase substrates: receptor-specific pattern of tyrosine phosphorylation and relationship to malignant transformation [13].

Anatomical context of Vil2

• Ezrin knockout (Vil2(-/-)) mice did not survive >1.5 wk after birth, making difficult to examine gastric acid secretion [1].
• Foxj1 is required for apical localization of ezrin in airway epithelial cells [14].
• Immunoelectron microscopy demonstrated ezrin associated with the basal bodies of cilia in the pulmonary epithelium [10].
• However, in differentiated cells, ezrin and moesin were selectively localized to apical membranes of ciliated airway cells and were absent from secretory cells [14].
• Microvilli defects in retinas of ezrin knockout mice [15].

Associations of Vil2 with chemical compounds

• Subcellular analysis demonstrated ezrin in fine filopodial structures in astrocytes, while merlin was detected in neuronal synaptic junctions [16].
• More interestingly, treatment with SB203580 induced elongation of microvilli and increased phosphorylation of ezrin (at Thr-567 and Tyr-353) [17].
• Phosphorylation of ezrin on threonine T567 plays a crucial role during compaction in the mouse early embryo [18].
• Alanine mutations of membrane-proximal basic amino acid residues in the cytoplasmic domain of L-selectin identified arginine 357 as a critical residue for both ezrin and moesin interaction [19].
• Ezrin is a cyclic AMP-dependent protein kinase anchoring protein [20].

Physical interactions of Vil2

• Ezrin binding domain-deficient NHERF attenuates cAMP-mediated inhibition of Na(+)/H(+) exchange in OK cells [21].
• Opossum kidney (OK) cells were transfected with either empty vector (control), full-length mouse (m) NHERF(1-355), or a truncated mNHERF(1-325) that lacked ezrin binding and had been demonstrated in fibroblasts to bind NHE3 but not mediate its cAMP-associated inhibition [21].

Enzymatic interactions of Vil2

• Two isoforms of ezrin phosphorylated on tyrosine residues are present during all of preimplantation development while a third non-tyrosine-phosphorylated isoform appears at the 8-cell stage and its relative amount increases from the 8-cell stage to the blastocyst stage [22].

Co-localisations of Vil2

• Phosphorylated ezrin-positive dots were colocalized with actin-positive dots on the surface of some Raf-1 transfectants treated with SB203580 [17].

Regulatory relationships of Vil2

• Phosphorylation of ezrin enhances microvillus length via a p38 MAP-kinase pathway in an immortalized mouse hepatic cell line [17].
• In addition, inhibitors of phosphatidylinositol 3-kinase and c-Src significantly blocked cell motility and invasion of AC2M2 cells expressing wild-type ezrin [4].
• Here, we show that the expression of TREK-1 markedly alters the cytoskeletal network and induces the formation of actin- and ezrin-rich membrane protrusions [23].

Other interactions of Vil2

• Additionally, following treatment of foxj1(-/-) tracheal explants with calpain inhibitor, basal bodies were observed in an apical location along with relocalization of ezrin and EBP-50 [10].
• By western blot and immunofluorescence, ezrin, a substrate for calpain, was also found to decrease in the pulmonary epithelium of foxj1(-/-) mice [10].
• Two-dimensional electrophoresis of our phosphorylated BBM proteins, followed by MALDI/MS analysis resulted in the identification of a protein mixture containing ezrin/moesin, alkaline phosphatase, and an unknown protein [11].
• Sequence analysis has demonstrated that mouse radixin shares 75.3% identity with human ezrin, which was reported to be a member of the band 4.1 family [24].
• Ectopic expression of PA2.26 in immortalized, nontumorigenic, keratinocytes induces an epithelial-fibroblastoid morphological conversion with increased plasma membrane extensions, concomitantly to a major reorganization of the actin cytoskeleton, redistribution of ezrin to cell-surface projections, and enhanced motility [25].

Analytical, diagnostic and therapeutic context of Vil2

• Based on Western and immunoprecipitation data for ezrin, moesin, and PDZ-dc1 we believe that it is unlikely that our phosphoprotein is any of these 3 proteins [11].
• Similar changes were seen following microinjection of anti-p81/ezrin antibody, suggesting that N-ezrin may function as a dominant negative competitor of ezrin [26].
• Gel filtration and chemical cross-linking studies demonstrated that ezrin exists mainly in the form of noncovalent dimers and higher order oligomers in extracts of placental microvilli [27].
• Gene array experiments, together with protein expression analysis by immunoblotting, revealed a differential spatiotemporal distribution of several proteins associated with epithelial maturation and polarization, including intercellular junctional proteins (e.g., ZO-1, claudin-3, E-cadherin) and the subapical cytoskeletal/microvillar protein ezrin [28].
• VECs were identified by location, morphology, ezrin staining, and electron microscopy [29].

References