PROTOCADHERIN 7 Acts through SET and PP2A to Potentiate MAPK Signaling by EGFR and KRAS during Lung Tumorigenesis.
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. Cancer Res; 77(1); 187-97. ©2016 AACR.
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.|Department of Immunology, Nantong University School of Medicine, Nantong, China.
Xiaorong
X
Zhou
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
Barrett L
BL
Updegraff
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
Yabin
Y
Guo
Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas.
Michael
M
Peyton
Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas.|Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas.
Luc
L
Girard
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland.
Jill E
JE
Larsen
Department of Clinical Science, UT Southwestern Medical Center, Dallas, Texas.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.
Xian-Jin
XJ
Xie
Department of Clinical Science, UT Southwestern Medical Center, Dallas, Texas.
Yunyun
Y
Zhou
Department of Clinical Science, UT Southwestern Medical Center, Dallas, Texas.
Tae Hyun
TH
Hwang
Department of Clinical Science, UT Southwestern Medical Center, Dallas, Texas.
Yang
Y
Xie
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jaime
J
Rodriguez-Canales
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Pamela
P
Villalobos
Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Carmen
C
Behrens
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ignacio I
II
Wistuba
Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas.|Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas.|Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas.
John D
JD
Minna
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas. Kathryn.ODonnell@UTSouthwestern.edu.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.
Kathryn A
KA
O'Donnell
D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins; D066246:ErbB Receptors / Q000378:metabolism; D064593:Heterografts; D056488:Histone Chaperones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D054648:Protein Phosphatase 2 / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D000091363:Protocadherins; D015398:Signal Transduction / Q000502:physiology; D016019:Survival Analysis; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism
D015820:Cadherins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C117307:KRAS protein, human; C113391:PCDH7 protein, human; D000091363:Protocadherins; C513473:SET protein, human; D014157:Transcription Factors; C512478:EGFR protein, human; D066246:ErbB Receptors; D054648:Protein Phosphatase 2; D016283:Proto-Oncogene Proteins p21(ras)