We show that TgWIP is secreted into the host cell upon invasion and interacts with the host WAVE regulatory complex and SHP2 phosphatase, both of which regulate actin dynamics.
Our data indicated that GOF-mutant SHP2 enhanced the abilities of GBM cells for proliferation, migration, and invasion in vitro, and promoted tumor growth in vivo.
In addition, SHP2 overexpression is associated with tumor stage and differentiation, enhanced cell proliferation and invasion, and tumorigenesis and metastasis.
Shp2 is also involved in several cancer-related processes, including cancer cell invasion and metastasis, apoptosis, DNA damage, cell proliferation, cell cycle and drug resistance.
Unbiased phosphoproteomics and biochemical analysis showed that SHP2 activates several SRC-family kinases and downstream targets, most of which are inducers of migration and invasion.
The effects of dual Src/SHP-2 functional inhibition were evaluated by Western blot analysis of downstream signaling pathways; cell biology assays to examine caspase activity, viability, adhesion, migration, and invasion in vitro; and an orthotopic nude mouse model to observe pancreatic tumor formation in vivo.
By expressing Gab2 wild-type and Gab2 mutants that are defective in activation of the PI3K and Shp2-Erk pathways, we find that Gab2 inhibits E-cadherin expression and enhances the expression of Zeb1, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), and cell migration and invasion through the activation of the PI3K pathway.
Recently, we reported that tyrosine-protein phosphatase non-receptor type 11 (SHP-2) and phosphatidylinositol 3-kinase (PI3K) mediate platelet-derived growth factor receptor-α (PDGFRα)-promoted glioma tumor growth and invasion.
Knockdown of SHP2 eradicated breast tumor-initiating cells in xenograft models, and SHP2 depletion also prevented invasion in three-dimensional cultures and in a transductal invasion assay in vivo.
In addition to activating Fyn, this interaction with Y580-SHP2 localizes Fyn to sites of receptor engagement, which is required for α6β4-dependent invasion.
Functional-blocking monoclonal antibody against integrins alpha(v)beta3, but not alpha2 alpha3, alpha4 alpha6 beta1, beta4 or alpha2beta1, inhibited the IGF-1-stimulated invasion and proliferation in cervical cancer cells. alpha(v)beta3 integrin modulated IGF-1R phosphorylation by altering the rate of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) recruitment to the activated IGF-1R.