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ERBIN MEDIATES SCHWANN CELL GROWTH AND DIFFERENTIATION

by RANGWALA, RESHMA

Abstract (Summary)
Erbin, a PDZ protein, was identified three years ago as an erbB2 interacting protein. It contains 16 leucine rich repeats in its amino terminus and a single PDZ domain in its carboxy terminus. It was originally believed to serve as a targeting protein; targeting the erbB2 receptor to the basolateral aspect of the cell. Since then studies have demonstrated that erbin can 1) modulate Ras/MAP kinase by interfering with Ras’ association with Raf 2) influence cell motility by modulating Rho signaling pathways 3) bind to a number of the p120 family of catenins, &beta-catenin, and the hemidesmosomal proteins integrin &beta4 and eBPAG1 4) can influence the integrity of the neuromuscular junction. Furthermore, studies have demonstrated that erbin’s interactions with members of the p120 family of catenins are far more robust than its interaction with erbB2 or &beta-catenin. In light of the observation that erbin can modulate Rho signaling and can bind to p120 catenins, &beta-catenin, and erbB2 we were interested in determining the role of erbin in the peripheral nerve, and specifically in the Schwann cell. The data described here suggest that erbin co-localizes with E-cadherin and &beta-catenin in the paranode of the peripheral nerve and is, therefore, a putative component of the autotypic adherens junction. Reduction in erbin expression in the Schwann using siRNA reveals that Schwann cells reduced in erbin expression exhibit 1) alterations in their prototypical bipolar morphology, 2) loss of cell-substrate adhesion 3) increased proliferation 4) a decrease in the hypophosphorylated form of merlin 5) decreased association between &beta-catenin and E-cadherin, &beta-catenin and merlin, and erbB2 and CD44 6) increased expression of phosphorylated &beta-catenin and E-cadherin 7) increased activation of ERK. Pharmacological inhibition of MEK, an ERK kinase, leads to a partial reversal of the alterations listed above suggesting that adherens junction instability following erbin reduction is MEK/ERK dependent. In vitro binding assays also demonstrate that EBP50, an ERM binding protein that contains two PDZ domains, directly interacts with erbin, thus serving as a bridge between merlin and &beta-catenin.
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School:University of Cincinnati

School Location:USA - Ohio

Source Type:Master's Thesis

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Date of Publication:01/01/2005

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