Promotion of Colorectal Cancer Invasion and Metastasis Through Activation of Notch-Dab1-Abl-RhoGEF Protein Trio
Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels la protéine multifonctionnelle Trio favorise le processus invasif et métastatique d'un cancer colorectal
We have recently identified a metastasis suppressor gene for colorectal cancer (CRC); AES/Aes which encodes an endogenous inhibitor of Notch signaling. When Aes is knocked out in the adenomatous epithelium of intestinal polyposis mice, their tumors become malignant, showing marked submucosal invasion and intravasation. Here we show that one of the genes induced by Notch signaling in CRC is DAB1/Dab1. Genetic depletion of Dab1 suppresses cancer invasion and metastasis in the Notch signaling-activated mice. Dab1 is phosphorylated by Abl tyrosine kinase, which activates Abl reciprocally. Consistently, inhibition of Abl suppresses cancer invasion in mice. Furthermore, we show that one of the targets of Abl Tyr-kinase is Rac/Rho-GEF protein Trio, and that phosphorylation at its Tyr residue 2681 (pY2681) causes Rho activation in CRC cells. Its unphosphorylatable mutation Trio(Y2681F) reduces the RhoGEF activity, and inhibits invasion of CRC cells. Importantly, Trio(pY2681) correlates with significantly poorer prognosis of CRC patients after surgery.