A novel RON splice variant lacking exon 2 activates the PI3K/AKT pathway via PTEN phosphorylation in colorectal carcinoma cells

作者：Ling, Yu; Kuang, Yeye; Chen, Lin-Lin; Lao, Wei-Feng; Zhu, Yao-Ru; Wang, Le-Qi; Wang, Da^*

来源：Oncotarget, 2017, 8(24): 39101-39116.

DOI：10.18632/oncotarget.16603

• RON
• splicing variants
• PTEN
• PI3K/AKT pathway
• colorectal cancer cell

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 premRNA splicing that eliminates exon 2, causing an in-frame deletion of 63 amino acids in the extracellular domain of the RON beta chain. The deleted transcript was a single chain expressed in the intracellular compartment. Although it lacked tyrosine phosphorylation activity, the RON Delta 165(E2) 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 RON Delta 165(E2) 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 RON Delta 165(E2) variant promoted tumor progression while activating the PI3K/AKT pathway via PTEN phosphorylation.

• 出版日期2017-6-13
• 单位杭州医学院; 浙江大学