2014 doi:ten.1093/carcin/bgu025 Advance Access publication January 30,SHP2E76K mutant
2014 doi:10.1093/carcin/bgu025 Advance Access publication January 30,SHP2E76K mutant promotes lung tumorigenesis in transgenic miceValentina E.Schneeberger1,2, Noreen Luetteke3, Yuan Ren1, Hartmut Berns3, Liwei Chen1, Parastou Foroutan3, Gary V.Martinez3, Eric B.Haura2,4,5, Jiandong Chen1,2,five, Domenico Coppola5,six and Jie Wu1,two,5,*Department of Molecular Oncology, H. Lee PDE11 Source Moffitt Cancer Center and Investigation Institute, 2Division of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, 3Small Animal Modeling and Imaging Core and 4Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Analysis Institute, 5Department of Oncologic Sciences, University of South Florida College of Medicine and 6Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Investigation Institute, Tampa, FL 33612, USA *To whom correspondence should be addressed. Department of Molecular Oncology, SRB-3, H. Lee Moffitt Cancer Center and Investigation Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. Tel: +1 813 745 6713; Fax: +1 813 745 3829; E-mail: jerry.wu@moffitt.orgLung cancer is usually a key disease carrying heterogeneous molecular lesions and numerous of them stay to be analyzed functionally in vivo. Gain-of-function (GOF) SHP2 (PTPN11) mutations have been found in numerous varieties of human cancer, including lung cancer. However, the part of activating SHP2 mutants in lung cancer has not been established. We generated transgenic mice containing a doxycycline (Dox)-inducible activating SHP2 mutant (tetO-SHP2E76K) and analyzed the function of SHP2E76K in lung tumorigenesis in the Clara cell secretory protein (CCSP)-reverse tetracycline transactivator (rtTA)/tetO-SHP2E76K bitransgenic mice. SHP2E76K activated Erk1/Erk2 (Erk1/2) and Src, and upregulated c-Myc and Mdm2 within the lungs of bitransgenic mice. Atypical adenomatous hyperplasia and smaller adenomas were observed in CCSP-rtTA/tetO-SHP2E76K bitransgenic mice induced with Dox for two months and progressed to larger adenoma and adenocarcinoma by 9 months. Dox withdrawal from bitransgenic mice bearing magnetic resonance imaging-detectable lung tumors resulted in tumor regression. These benefits show that the activating SHP2 mutant promotes lung tumorigenesis and that the SHP2 mutant is expected for tumor maintenance in this mouse model of non-small cell lung cancer. SHP2E76K was associated with Gab1 inside the lung of transgenic mice. Elevated pGab1 was observed within the lung of Dox-induced CCSP-rtTA/tetO-SHP2E76K mice and in cell lines expressing SHP2E76K, indicating that the activating SHP2 mutant autoregulates tyrosine PDGFR Species phosphorylation of its own docking protein. Gab1 tyrosine phosphorylation is sensitive to inhibition by the Src inhibitor dasatinib in GOF SHP2-mutantexpressing cells, suggesting that Src loved ones kinases are involved in SHP2 mutant-induced Gab1 tyrosine phosphorylation.Introduction Because protein tyrosine phosphatases (PTPs) counter the biochemical reaction of protein tyrosine kinases (PTKs) and a lot of PTKs have oncogenic activity, PTPs have been mainly perceived as tumor suppressors. Having said that, rising evidence suggests that in some circumstances PTPs cooperate with PTKs to market cell signaling and oncogenesis (1,two). It is identified that particular tyrosine phosphorylation web-sites exert an inhibitoryAbbreviations: CCSP, Clara cell secretory protein; Dox, doxycyline; EGFR, epidermal growth element receptor; GOF, gain-of-function; H E, hematoxylin and eosin; mRNA, messenger RNA; MRI, magnetic resonance.
