ABI3, a component of the WAVE2 complex, is potentially regulated by PI3K/AKT pathway.

Lais Moraes,Janete M. Cerutti,Nilson I.T. Zanchin

doi:10.18632/oncotarget.18840

Lais Moraes, Janete M. Cerutti + Show 1 more

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https://doi.org/10.18632/oncotarget.18840

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Abstract

We previously reported that ABI3 expression is lost in follicular thyroid carcinomas and its restoration significantly inhibited cell growth, invasiveness, migration, and reduced tumor growth in vivo. The mechanistic basis by which ABI3 exerts its tumor suppressive effects is not fully understood. In this study, we show that ABI3 is a phosphoprotein. Using proteomic array analysis, we showed that ABI3 modulated distinct cancer-related pathways in thyroid cancer cells. The KEA analysis found that PI3K substrates were enriched and forced expression of ABI3 markedly decreased the phosphorylation of AKT and the downstream-targeted protein pGSK3β. We next used immunoprecipitation combined with mass spectrometry to identify ABI3-interacting proteins that may be involved in modulating/integrating signaling pathways. We identified 37 ABI3 partners, including several components of the canonical WAVE regulatory complex (WRC) such as WAVE2/CYF1P1/NAP1, suggesting that ABI3 function might be regulated through WRC. Both, pharmacological inhibition of the PI3K/AKT pathway and mutation at residue S342 of ABI3, which is predicted to be phosphorylated by AKT, provided evidences that the non-phosphorylated form of ABI3 is preferentially present in the WRC protein complex. Collectively, our findings suggest that ABI3 might be a downstream mediator of the PI3K/AKT pathway that might disrupt WRC via ABI3 phosphorylation.

Highlights

We previously reported that ABI3 (ABL-Interactor member 3) expression is lost in most thyroid carcinomas, compared to benign lesions and normal thyroid tissues
We previously reported that ABI3 expression is lost in follicular thyroid carcinomas and its restoration significantly inhibited cell growth, invasiveness, migration, and reduced tumor growth in vivo
As the experimental results presented above suggest that WAVE2 and CYF1P1 directly interact with ABI3 and that PI3K/AKT pathway may regulates the basal activity of ABI3, we investigate whether PI3K/AKT inhibitors may affect protein interactions

Summary

Introduction

We previously reported that ABI3 (ABL-Interactor member 3) expression is lost in most thyroid carcinomas, compared to benign lesions and normal thyroid tissues. ABI3 re-expression in a human follicular thyroid carcinoma cell line significantly inhibited cell proliferation, invasion, and migration in vitro and reduced tumor growth in vivo. We demonstrated that transcriptional silencing of ABI3 in thyroid cancer occurs via methylation of specific GpG sites located within the ABI3 promoter [2]. These findings suggested that ABI3 act as a tumor suppressor gene. In addition to its suppressive role in thyroid cancer, it has been demonstrated that ABI3 expression is frequently lost in invasive cancer cell lines. DNA methylation and transcriptional silencing of ABI3 was associated with poorprognosis in chronic lymphocytic leukemia samples [7]

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