Lyn, a Src family kinase, regulates activation of epidermal growth factor receptors in lung adenocarcinoma cells

Molecular Cancer

Research

Jeffrey A Borgia¹  Parnetta Sutton²  Philip Bonomi³  Janet MD Plate⁴ 

[1] Department of Biochemistry, Rush University Medical Center, 60612, Chicago, IL, USA;Department of Medical Laboratory Sciences, Rush University Medical Center, 60612, Chicago, IL, USA;Division of Oncology, Department of Medicine, Hematology and Cell Therapy, Rush University Medical Center, 60612, Chicago, IL, USA;Division of Oncology, Department of Medicine, Hematology and Cell Therapy, Rush University Medical Center, 60612, Chicago, IL, USA;Division of Oncology, Department of Medicine, Hematology and Cell Therapy, Rush University Medical Center, 60612, Chicago, IL, USA;Department of Immunology & Microbiology, Rush University Medical Center, 60612, Chicago, IL, USA;

关键词: Lung adenocarcinoma cells;    Epidermal growth factor receptors;    Src family kinases;    Lyn;    Membrane-associated protein complexes/lipid rafts;    RACK1;    Cbp\PAG;   

DOI  :  10.1186/1476-4598-12-76

 received in 2012-06-25, accepted in 2013-07-12,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundActivation of receptors for growth factors on lung epithelial cells is essential for transformation into tumor cells, supporting their viability and proliferation. In most lung cancer patients, EGFR is constitutively activated without evidence of mutation. Defining mechanisms for constitutive activation of EGFR could elucidate additional targets for therapy of lung cancers.MethodsThe approach was to identify lung cancer cell lines with constitutively activated EGFR and use systematic selection of inhibitors to evaluate their effects on specific EGFR phosphorylations and downstream signaling pathways. Interactions between receptors, kinases, and scaffolding proteins were investigated by co-immunoprecipitation plus Western blotting.ResultsThe results revealed a dependence on Src family of tyrosine kinases for downstream signaling and cell growth. Lyn, a Src family kinase functional in normal and malignant B-lymphocytes, was a defining signal transducer required for EGFR signaling in Calu3 cell line. Src family kinase activation in turn, was dependent on PKCßII. Lyn and PKC exist in membrane complexes of RACK1 and in association with EGFR which pairs with other receptor partners. Silencing of Lyn expression with interfering siRNA decreased EGFR activation and cell viability.ConclusionsThe importance of Src family kinases and PKCßII in the initiation of the EGFR signaling pathway in lung tumor cells was demonstrated. We conclude that phosphorylation of EGFR is mediated through PKCßII regulation of Lyn activation, and occurs in association with RACK1 and Cbp/PAG proteins. We suggest that protein complexes in cell membranes, including lipid rafts, may serve as novel targets for combination therapies with EGFR and Src Family Kinase inhibitors in lung cancer.

【 授权许可】

Unknown   
© Sutton et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.