title: A novel RON splice variant lacking exon 2 activates the PI3K/AKT pathway via PTEN phosphorylation in colorectal carcinoma cells.
abstract: Abnormal expression of the Recepteur d'Origine Nantais (RON) receptor tyrosine kinase is accompanied by the generation of multiple splice or truncated variants, which mediate many critical cellular functions that contribute to tumor progression and metastasis. Here, we report a new RON splice variant in the human colorectal cancer (CRC) cell line HT29. This variant is a 165 kda protein generated by alternative pre-mRNA splicing that eliminates exon 2, causing an in-frame deletion of 63 amino acids in the extracellular domain of the RON β chain. The deleted transcript was a single chain expressed in the intracellular compartment. Although it lacked tyrosine phosphorylation activity, the RONΔ165E2 variant could phosphorylate phosphatase and tensin homolog (PTEN), thereby activating the PI3K/AKT pathway. In addition, in vitro and in vivo experiments showed that the RONΔ165E2 promoted cell migration and tumor growth. Finally, in an investigation of 67 clinical CRC samples, the variant was highly expressed in about 58% of the samples, and was positively correlated with the invasive depth of the tumor (P < 0.05). These results demonstrate that the novel RONΔ165E2 variant promoted tumor progression while activating the PI3K/AKT pathway via PTEN phosphorylation.
authors.affiliation: Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University of Medicine, Hangzhou, Zhejiang 310016, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Biomedical Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Yeye
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University of Medicine, Hangzhou, Zhejiang 310016, People's Republic of China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Chen
authors.affiliation: Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University of Medicine, Hangzhou, Zhejiang 310016, People's Republic of China.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Lao
authors.affiliation: Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University of Medicine, Hangzhou, Zhejiang 310016, People's Republic of China.
authors.forename: Yao-Ru
authors.initials: YR
authors.lastname: Zhu
authors.affiliation: Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University of Medicine, Hangzhou, Zhejiang 310016, People's Republic of China.
authors.forename: Le-Qi
authors.initials: LQ
authors.lastname: Wang
authors.affiliation: Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University of Medicine, Hangzhou, Zhejiang 310016, People's Republic of China.
authors.forename: Da
authors.initials: D
authors.lastname: Wang
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PI3K/AKT pathway; PTEN; RON; colorectal cancer cell; splicing variants