The role of cooperativity with Src in oncogenic transformation mediated by non-small cell lung cancer-associated EGF receptor mutants

被引:42
作者
Chung, B. M. [1 ,5 ,6 ]
Dimri, M. [5 ,6 ]
George, M. [1 ,5 ,6 ]
Reddi, A. L. [5 ,6 ]
Chen, G. [5 ,6 ]
Band, V. [3 ,4 ,5 ,6 ]
Band, H. [1 ,2 ,3 ,4 ,5 ,6 ]
机构
[1] Univ Nebraska Med Ctr, Eppley Inst Canc & Allied Dis, Nebraska Med Ctr, Omaha, NE 68198 USA
[2] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Nebraska Med Ctr, Omaha, NE 68198 USA
[3] Univ Nebraska Med Ctr, Coll Med, Dept Genet Cell Biol & Anat, Nebraska Med Ctr, Omaha, NE 68198 USA
[4] Univ Nebraska Med Ctr, UNMC Eppley Canc Ctr, Nebraska Med Ctr, Omaha, NE 68198 USA
[5] Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Feinberg Sch Med, Evanston NW Healthcare Res Inst,Dept Med, Evanston, IL USA
[6] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL USA
关键词
mutant EGFR; Src; transformation; GROWTH-FACTOR-RECEPTOR; C-SRC; KINASE INHIBITOR; SIGNAL TRANSDUCERS; TYROSINE KINASES; DOWN-REGULATION; MUTATIONS; ACTIVATION; GEFITINIB; SURVIVAL;
D O I
10.1038/onc.2009.31
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Non-small cell lung cancer (NSCLC)-associated epidermal growth factor receptor (EGFR) mutants are constitutively active and induce ligand-independent transformation in non-malignant cell lines. We investigated the possibility that the ability of mutant EGFRs to transform cells reflects a constitutive cooperativity with Src using a system in which the overexpression of mutant, but not wild-type, EGFR induced anchorage-independent cell growth. Src was constitutively activated and showed enhanced interaction with mutant EGFRs, suggesting that constitutive EGFR-Src cooperativity may contribute to mutant EGFR-mediated oncogenesis. Indeed, the mutant EGFR-mediated cell transformation was inhibited by Src- as well as EGFR-directed inhibitors. Importantly, a tyrosine to phenylalanine mutation of the major Src phosphorylation site on EGFR, Y845, reduced the constitutive phosphorylation of NSCLC-EGFR mutants, as well as that of STAT3, Akt, Erk and Src, and reduced the mutant EGFR-Src association as well as proliferation, migration and anchorage-independent growth. Reduced anchorage-independent growth and migration were also observed when dominant-negative-Src was expressed in mutant EGFR-expressing cells. Overall, our findings show that mutant EGFR-Src interaction and cooperativity play critical roles in constitutive engagement of the downstream signaling pathways that allow NSCLC-associated EGFR mutants to mediate oncogenesis, and support the rationale to target Src- dependent signaling pathways in mutant EGFR-mediated malignancies.
引用
收藏
页码:1821 / 1832
页数:12
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