Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation

Junmei Cairns, Brooke L. Fridley, Gregory D. Jenkins, Yongxian Zhuang, Jia Yu, Liewei Wang

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

AKT signaling is modulated by a complex network of regulatory proteins and is commonly deregulated in cancer. Here, we present a dual mechanism of AKT regulation by the ERBB receptor feedback inhibitor 1 (ERRFI1). We show that in cells expressing high levels of EGFR, ERRF1 inhibits growth and enhances responses to chemotherapy. This is mediated in part through the negative regulation of AKT signaling by direct ERRFI1-dependent inhibition of EGFR. In cells expressing low levels of EGFR, ERRFI1 positively modulates AKT signaling by interfering with the interaction of the inactivating phosphatase PHLPP with AKT, thereby promoting cell growth and chemotherapy desensitization. These observations broaden our understanding of chemotherapy response and have important implications for the selection of targeted therapies in a cell context-dependent manner. EGFR inhibition can only sensitize EGFR-high cells for chemotherapy, while AKT inhibition increases chemosensitivity in EGFR-low cells. By understanding these mechanisms, we can take advantage of the cellular context to individualize antineoplastic therapy. Finally, our data also suggest targeting of EFFRI1 in EGFR-low cancer as a promising therapeutic approach.

Original languageEnglish (US)
Article numbere44767
JournalEMBO Reports
Volume19
Issue number3
DOIs
StatePublished - Mar 2018

Keywords

  • AKT
  • AKT inhibitor
  • EGFR
  • ERRFI1
  • PHLPP

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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