Abstract
Epidermal growth factor receptor (EGFR) mutants drive lung tumorigenesis and are targeted for therapy. However, resistance to EGFR inhibitors has been observed, in which the mutant EGFR remains active. Thus, it is important to uncover mediators of EGFR mutant-driven lung tumors to develop new treatment strategies. The protein tyrosine phosphatase (PTP) Shp2 mediates EGF signaling. Nevertheless, it is unclear if Shp2 is activated by oncogenic EGFR mutants in lung carcinoma or if inhibiting the Shp2 PTP activity can suppress EGFR mutant-induced lung adenocarcinoma. Here, we generated transgenic mice containing a doxycycline (Dox)-inducible PTP-defective Shp2 mutant (tetO-Shp2CSDA). Using the rat Clara cell secretory protein (CCSP)-rtTA-directed transgene expression in the type II lung pneumocytes of transgenic mice, we found that the Gab1-Shp2 pathway was activated by EGFRL858R in the lungs of transgenic mice. Consistently, the Gab1-Shp2 pathway was activated in human lung adenocarcinoma cells containing mutant EGFR. Importantly, Shp2CSDA inhibited EGFRL858R-induced lung adenocarcinoma in transgenic animals. Analysis of lung tissues showed that Shp2CSDA suppressed Gab1 tyrosine phosphorylation and Gab1-Shp2 association, suggesting that Shp2 modulates a positive feedback loop to regulate its own activity. These results show that inhibition of the Shp2 PTP activity impairs mutant EGFR signaling and suppresses EGFRL858R-driven lung adenocarcinoma.
Highlights
Shp2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the human PTPN11 gene [1]
Tissues from both C/S65/EL858R and C/S669/ EL858R tritransgenic mice displayed markedly decreased pGab1 and Gab1-bound Shp2 (Fig. 6D). These results indicate that Shp2CSDA competed with the endogenous Shp2 for Gab1 binding and reduced Gab1 phosphorylation at the Shp2 binding site, preventing binding and activation of the endogenous Shp2 by EGFRL858R in the lungs of tritransgenic mice. It was previously unclear whether Shp2 is activated by oncogenic Epidermal growth factor receptor (EGFR) mutants and whether inhibition of the Shp2 PTP activity can suppress lung tumorigenesis in vivo
We found that endogenous Shp2 is activated in the lung tissues of transgenic mice in vivo by the EGFRL858R mutant
Summary
Shp is a nonreceptor PTP encoded by the human PTPN11 gene [1]. It has tandem SH2 domains in the N-terminal region, a PTP domain, and a C-terminal region containing tyrosine phosphorylation sites. Binding of Shp SH2 domains to specific tyrosine phosphorylated sites relieves autoinhibition and activates Shp. In epidermal growth factor (EGF)-stimulated cells, Shp binds to tyrosine-phosphorylated Gab at the bisphosphoryl tyrosine-based activation motif (BTAM) consisting of phosphorylated Tyr-627 and Tyr-659 [2]. Gab1-Shp binding activates the Shp PTP activity and mediates activation of Erk1/2 and Src family kinases (SFKs) by EGF [2,3,4,5]. In addition to EGFR, EGF paradoxically activates a PTP to mediate the EGFR protein tyrosine kinase (PTK) signaling
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