Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop.
Bottom Line: A similar effect was observed following treatment with c-Met inhibitor SU11274.Depletion of CRK significantly decreased cell proliferation of 5637 and UM-UC-3, consistent with reduced activity of ERK.An orthotopic xenograft model with bioluminescent imaging revealed that CRK knockdown significantly attenuated not only tumor volume but also the number of circulating tumor cells, resulted in a complete abrogation of metastasis.
Affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.Show MeSH
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Mentions: CRK is involved in diverse signaling transduction derived from various receptor tyrosine kinases such as epidermal growth factor receptor, fibroblast growth factor receptor, c-Met, nerve growth factor receptor, and platelet-derived growth factor receptor, cooperating with adaptor molecules such as IRS-1, Gab1, and Cbl.18–20 To identify CRK-associated signaling in invasive BC cells, the phosphorylation status of several receptor tyrosine kinases and downstream molecules were examined in the presence or absence of CRK-I/-II. The phosphorylation level of c-Met was definitely decreased by CRK elimination, whereas those of epidermal growth factor receptor and platelet-derived growth factor receptor-α were constant (Fig.4a). Src, FAK, and Gab1 have been shown to play a role in integrating signals from c-Met, coordinating with CRK.7,11,21 Indeed, the reduction of phosphorylation levels of Src and Gab1 was detected in Crk-depleted cells (Fig.4b). It is noteworthy that Crk knockdown significantly decreased expression levels of HGF mRNA, a ligand of the c-Met receptor (Fig.4c). Taken together, in invasive BC, CRK contributes to promote c-Met signaling by facilitating Gab1/p130Cas/Src complex assembly in focal adhesion and, ultimately, HGF expression.
Affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.