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

15 Citations (Scopus)

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

Fingerprint

Carcinogenesis
Non-Small Cell Lung Carcinoma
Lung
Neoplasms
Phosphoprotein Phosphatases
Oncogene Proteins
Mitogen-Activated Protein Kinase Kinases
Cell Surface Receptors
Growth
Membrane Proteins
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

PROTOCADHERIN 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis. / Zhou, Xiaorong; Updegraff, Barrett L.; Guo, Yabin; Peyton, Michael; Girard, Luc; Larsen, Jill E.; Xie, Xian-Jin; Zhou, Yunyun; Hwang, Tae Hyun; Xie, Yang; Rodriguez-Canales, Jaime; Villalobos, Pamela; Behrens, Carmen; Wistuba, Ignacio I.; Minna, John D; O'Donnell-Mendell, Kathryn A.

In: Cancer Research, Vol. 77, No. 1, 01.01.2017, p. 187-197.

Research output: Contribution to journalArticle

Zhou, X, Updegraff, BL, Guo, Y, Peyton, M, Girard, L, Larsen, JE, Xie, X-J, Zhou, Y, Hwang, TH, Xie, Y, Rodriguez-Canales, J, Villalobos, P, Behrens, C, Wistuba, II, Minna, JD & O'Donnell-Mendell, KA 2017, 'PROTOCADHERIN 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis', Cancer Research, vol. 77, no. 1, pp. 187-197. https://doi.org/10.1158/0008-5472.CAN-16-1267-T
Zhou, Xiaorong ; Updegraff, Barrett L. ; Guo, Yabin ; Peyton, Michael ; Girard, Luc ; Larsen, Jill E. ; Xie, Xian-Jin ; Zhou, Yunyun ; Hwang, Tae Hyun ; Xie, Yang ; Rodriguez-Canales, Jaime ; Villalobos, Pamela ; Behrens, Carmen ; Wistuba, Ignacio I. ; Minna, John D ; O'Donnell-Mendell, Kathryn A. / PROTOCADHERIN 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis. In: Cancer Research. 2017 ; Vol. 77, No. 1. pp. 187-197.
@article{0f3d0a194f6d45c08616ee4921b5241e,
title = "PROTOCADHERIN 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis",
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.",
author = "Xiaorong Zhou and Updegraff, {Barrett L.} and Yabin Guo and Michael Peyton and Luc Girard and Larsen, {Jill E.} and Xian-Jin Xie and Yunyun Zhou and Hwang, {Tae Hyun} and Yang Xie and Jaime Rodriguez-Canales and Pamela Villalobos and Carmen Behrens and Wistuba, {Ignacio I.} and Minna, {John D} and O'Donnell-Mendell, {Kathryn A}",
year = "2017",
month = "1",
day = "1",
doi = "10.1158/0008-5472.CAN-16-1267-T",
language = "English (US)",
volume = "77",
pages = "187--197",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - PROTOCADHERIN 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis

AU - Zhou, Xiaorong

AU - Updegraff, Barrett L.

AU - Guo, Yabin

AU - Peyton, Michael

AU - Girard, Luc

AU - Larsen, Jill E.

AU - Xie, Xian-Jin

AU - Zhou, Yunyun

AU - Hwang, Tae Hyun

AU - Xie, Yang

AU - Rodriguez-Canales, Jaime

AU - Villalobos, Pamela

AU - Behrens, Carmen

AU - Wistuba, Ignacio I.

AU - Minna, John D

AU - O'Donnell-Mendell, Kathryn A

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85009250525&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85009250525&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-16-1267-T

DO - 10.1158/0008-5472.CAN-16-1267-T

M3 - Article

C2 - 27821484

AN - SCOPUS:85009250525

VL - 77

SP - 187

EP - 197

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 1

ER -