PHLDA2 is a key oncogene-induced negative feedback inhibitor of EGFR/ErbB2 signaling via interference with AKT signaling.

Xiaoqi Wang,Matthew Maurer,Balazs Halmos,Rieko Ohki,Alain Borczuk,Guangyuan Li,Sanjay Koul

doi:10.18632/oncotarget.3674

Abstract

Pleckstrin homology-like domain family A member 2 (PHLDA2) is located within the tumor suppressor region of 11p15, and its expression is suppressed in several malignant tumor types. We recently identified PHLDA2 as a robustly induced, novel downstream target of oncogenic EGFR/ErbB2 signaling. In an immunohistochemical study, we find that PHLDA2 protein expression correlates positively with AKT activation in human lung cancers corroborating our data that PHLDA2 is induced upon oncogenic activation and might serve as a biomarker for AKT pathway activation. We show that PHLDA2 overexpression inhibits AKT phosphorylation while decreased PHLDA2 expression increases AKT activity. We further find that PHLDA2 competes with the PH domain of AKT for binding of membrane lipids, thereby directly inhibiting AKT translocation to the cellular membrane and subsequent activation. Indeed, PHLDA2 overexpression suppresses anchorage-independent cell growth and decreased PHLDA2 expression results in increased cell proliferation and reduced sensitivity to targeted agents of EGFR/ErbB2-driven cancers demonstrating functional relevance for this interaction. In summary, our studies demonstrate that PHLDA2 is strongly regulated by EGFR/ErbB2 signaling and inhibits cell proliferation via repressing AKT activation in lung cancers in a negative feedback loop. We highlight a novel action for PHLDA2 as a potential biomarker for AKT pathway activation.

Highlights

The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs) is a well-established target for anticancer therapies
We find that Pleckstrin homology-like domain family A member 2 (PHLDA2) protein expression correlates positively with AKT activation in human lung cancers corroborating our data that PHLDA2 is induced upon oncogenic activation and might serve as a biomarker for AKT pathway activation
As PHLDA2 is repetitively included in this group, we decided to focus on this novel downstream target gene that previously was not noted to be involved in EGFR/ErbB2-driven pathways

Summary

INTRODUCTION

The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs) is a well-established target for anticancer therapies. EGFR-mutated lung adenocarcinomas and ErbB2-positive breast and other cancers (such as gastric and lung) are critically dependent on the constitutive activity of these pathways and therapeutic targeting leads to significant clinical benefits [3,4,5,6]. In order to arrive at a comprehensive view of downstream signaling changes, we previously completed several transcriptional profiling studies identifying key groups of early EGFR and ErbB2 oncogenic pathway target genes. As our transcriptional profiling studies consistently found PHLDA2 as an immediate downstream target of EGFR/ErbB2 signaling, we speculated that PHLDA2 might have key inhibitory functions in EGFR and ErbB2-driven cancer cells and a better understanding of its functions might help define novel therapeutic options, in particular through yielding novel ways of interfering with phosphatidyl inositol-mediated activation of oncogenic AKT-driven pathways

RESULTS

DISCUSSION

MATERIALS AND METHODS

Acknowledgment and funding