Abstract
Aberrant signaling of receptor tyrosine kinases (RTKs), including the hepatocyte growth factor receptor MET, contributes to colorectal cancer (CRC) progression and is tightly regulated by endocytic trafficking. We previously showed that combined deletion of the endosomal sorting proteins SNX1 and SNX2 disrupts MET trafficking and enhances downstream signaling in HCT116 CRC cells. However, their individual contributions remained unresolved. Using CRISPR/Cas9-engineered SNX1- and SNX2-KO HCT116 cells, we examined their roles in MET trafficking and signaling.
Loss of SNX2, but not SNX1, markedly reduced SNX5 and SNX6 protein levels without affecting transcript abundance. SNX2 deficiency also increased total MET under serum-containing conditions without altering MET transcript or cell-surface receptor levels. Following HGF stimulation, loss of SNX2, but not SNX1, transiently delayed MET trafficking to EEA1+ early and RAB7+ late endosomes, while recycling and lysosomal trafficking remained largely unaffected. This was accompanied by enhanced and sustained HGF-induced AKT activation.
Together, these findings identify SNX2 as a predominant regulator of early MET endosomal trafficking in HCT116 cells and reveal functional asymmetry between SNX1 and SNX2. They support a role for SNX2 in spatial regulation of MET signaling through receptor trafficking, consistent with the association of low SNX2 expression with poorer survival in CRC patients.