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

// Xiaoqi Wang 1 , Guangyuan Li 1, 4 , Sanjay Koul 1 , Rieko Ohki 2 , Matthew Maurer 1 , Alain Borczuk 3 , Balazs Halmos 1 1 Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA 2 Radiobiology Division, National Cancer Center Research Institute, Tokyo, Japan 3 Department of Pathology, Columbia University Medical Center, New York, NY, USA 4 Department of Pathology, University Hospitals of Case Medical Center, Case Western Reserve University, Cleveland, OH, USA Correspondence to: Balazs Halmos, email: bh2376@columbia.edu Keywords: PHLDA2, EGFR, ErbB2, AKT Received: February 01, 2015 Accepted: March 24, 2015 Epub: April 09, 2015 Published: May 18, 2018 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.