AKT3-mediated IWS1 Phosphorylation Promotes the Proliferation of EGFR-mutant Lung Adenocarcinomas Through Cell Cycle-regulated U2AF2 RNA Splicing

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jul 31

PMID 34330897

Citations 7

Authors

Georgios I Laliotis

Evangelia Chavdoula

Maria D Paraskevopoulou

Abdul Kaba

Alessandro La Ferlita

Satishkumar Singh

Vollter Anastas

Keith A Nair 2nd

Arturo Orlacchio

Vasiliki Taraslia

Ioannis Vlachos

Marina Capece

Artemis Hatzigeorgiou

Dario Palmieri

Christos Tsatsanis

Salvatore Alaimo

Lalit Sehgal

David P Carbone

Vincenzo Coppola

Philip N Tsichlis

Affiliations

Soon will be listed here.

Abstract

AKT-phosphorylated IWS1 regulates alternative RNA splicing via a pathway that is active in lung cancer. RNA-seq studies in lung adenocarcinoma cells lacking phosphorylated IWS1, identified a exon 2-deficient U2AF2 splice variant. Here, we show that exon 2 inclusion in the U2AF2 mRNA is a cell cycle-dependent process that is regulated by LEDGF/SRSF1 splicing complexes, whose assembly is controlled by the IWS1 phosphorylation-dependent deposition of histone H3K36me3 marks in the body of target genes. The exon 2-deficient U2AF2 mRNA encodes a Serine-Arginine-Rich (RS) domain-deficient U2AF65, which is defective in CDCA5 pre-mRNA processing. This results in downregulation of the CDCA5-encoded protein Sororin, a phosphorylation target and regulator of ERK, G2/M arrest and impaired cell proliferation and tumor growth. Analysis of human lung adenocarcinomas, confirmed activation of the pathway in EGFR-mutant tumors and showed that pathway activity correlates with tumor stage, histologic grade, metastasis, relapse after treatment, and poor prognosis.

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