2. Academic Validation
  3. Phosphorylation of PLCγ1 by EphA2 Receptor Tyrosine Kinase Promotes Tumor Growth in Lung Cancer

Phosphorylation of PLCγ1 by EphA2 Receptor Tyrosine Kinase Promotes Tumor Growth in Lung Cancer

  • Mol Cancer Res. 2020 Nov;18(11):1735-1743. doi: 10.1158/1541-7786.MCR-20-0075.
Wenqiang Song  # 1 2,  Laura C Kim  # 3,  Wei Han 4,  Yuan Hou 5,  Deanna N Edwards 1,  Shan Wang 1,  Timothy S Blackwell 2 4 6,  Feixiong Cheng 5 7 8,  Dana M Brantley-Sieders 9 10,  Jin Chen 9 2 3 6 10
Affiliations

Affiliations

  • 1 Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
  • 2 Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee.
  • 3 Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee.
  • 4 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
  • 5 Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • 6 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
  • 7 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio.
  • 8 Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
  • 9 Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. jin.chen@vumc.org dana.brantley@vumc.org.
  • 10 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
  • # Contributed equally.
PMID: 32753469 DOI: 10.1158/1541-7786.MCR-20-0075
Abstract

EphA2 receptor tyrosine kinase (RTK) is often expressed at high levels in Cancer and has been shown to regulate tumor growth and metastasis across multiple tumor types, including non-small cell lung Cancer. A number of signaling pathways downstream of EphA2 RTK have been identified; however, mechanisms of EphA2 proximal downstream signals are less well characterized. In this study, we used a yeast-two-hybrid screen to identify Phospholipase C gamma 1 (PLCγ1) as a novel EphA2 interactor. EphA2 interacts with PLCγ1 and the kinase activity of EphA2 was required for phosphorylation of PLCγ1. In human lung Cancer cells, genetic or pharmacologic inhibition of EphA2 decreased phosphorylation of PLCγ1 and loss of PLCγ1 inhibited tumor cell growth in vitro. Knockout of PLCγ1 by CRISPR-mediated genome editing also impaired tumor growth in a KrasG12D-p53-Lkb1 murine lung tumor model. Collectively, these data show that the EphA2-PLCγ1 signaling axis promotes tumor growth of lung Cancer and provides rationale for disruption of this signaling axis as a potential therapeutic option. IMPLICATIONS: The EphA2-PLCG1 signaling axis promotes tumor growth of non-small cell lung Cancer and can potentially be targeted as a therapeutic option.

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