A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells.

摘要: The MST1R gene is overexpressed in pancreatic cancer producing elevated levels of the RON tyrosine kinase receptor protein. While mutations are rare, alternative splice variants have been previously reported epithelial cancers. We report discovery a novel isoform discovered human cancer. Partial splicing exons 5 and 6 (P5P6) produces that lacks first extracellular immunoglobulin-plexin-transcription domain. variant detected 73% xenografts derived from adenocarcinoma patients 71% cell lines. Peptides specific to P5P6 specimens by mass spectrometry confirm translation protein isoform. found be constitutively phosphorylated, present cytoplasm, it traffics plasma membrane. Expression immortalized duct (HPDE) cells activates downstream AKT, nestin-expressing cells, both AKT MAPK pathways. Inhibiting HPDE using small molecule inhibitor BMS-777607 blocked constitutive activation decreased signaling. transforms NIH3T3 induces tumorigenicity cells. Resultant HPDE-P5P6 tumors develop dense stromal compartment similar seen In summary, we identified active has transforming activity expressed These findings provide additional insight into biology clinically relevant study as potential therapeutic target.