PROTOCADHERIN 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis

Xiaorong Zhou, Barrett L. Updegraff, Yabin Guo, Michael Peyton, Luc Girard, Jill E. Larsen, Xian-Jin Xie, Yunyun Zhou, Tae Hyun Hwang, Yang Xie, Jaime Rodriguez-Canales, Pamela Villalobos, Carmen Behrens, Ignacio I. Wistuba, John D Minna, Kathryn A O'Donnell-Mendell

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated deaths worldwide. Given the efficacy of membrane proteins as therapeutic targets in human malignancies, we examined cell-surface receptors that may act as drivers of lung tumorigenesis. Here, we report that the PROTOCADHERIN PCDH7 is overexpressed frequently in NSCLC tumors where this event is associated with poor clinical outcome. PCDH7 overexpression synergized with EGFR and KRAS to induce MAPK signaling and tumorigenesis. Conversely, PCDH7 depletion suppressed ERK activation, sensitized cells to MEK inhibitors, and reduced tumor growth. PCDH7 potentiated ERK signaling by facilitating interaction of protein phosphatase PP2A with its potent inhibitor, the SET oncoprotein. By establishing an oncogenic role for PCDH7 in lung tumorigenesis, our results provide a rationale to develop novel PCDH7 targeting therapies that act at the cell surface of NSCLC cells to compromise their growth.

Original languageEnglish (US)
Pages (from-to)187-197
Number of pages11
JournalCancer research
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zhou, X., Updegraff, B. L., Guo, Y., Peyton, M., Girard, L., Larsen, J. E., Xie, X-J., Zhou, Y., Hwang, T. H., Xie, Y., Rodriguez-Canales, J., Villalobos, P., Behrens, C., Wistuba, I. I., Minna, J. D., & O'Donnell-Mendell, K. A. (2017). PROTOCADHERIN 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis. Cancer research, 77(1), 187-197. https://doi.org/10.1158/0008-5472.CAN-16-1267-T