PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation

作者：Hongxia Chen, Yunpeng Bai, Michihiro Kobayashi, Shiyu Xiao, Sergio Barajas, Wenjie Cai, Sisi Chen, Jinmin Miao, Frederick Nguele Meke, Chonghua Yao, Yuxia Yang, Katherine Strube, Odelia Satchivi, Jianmin Sun, Lars Rönnstrand, James M. Croop, H. Scott Boswell, Yuzhi Jia, Huiping Liu, Loretta S. Li, Jessica K. Altman, Elizabeth A. Eklund, Madina Sukhanova, Peng Ji, Wei Tong, Hamid Band, Danny T. Huang, Leonidas C. Platanias, Zhong-Yin Zhang, Yan Liu · 发表于：Molecular Cancer Research · 年份：2023 · DOI：10.1158/1541-7786.mcr-23-0115 · 被引用次数：5 · 研究领域：Protein Tyrosine Phosphatases、Chronic Myeloid Leukemia Treatments、Acute Myeloid Leukemia Research

Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells. IMPLICATIONS: Our studies uncover a novel mechanism that fine-tunes oncogenic KIT signaling in leukemia cells and will likely identify PRL2 as a novel therapeutic target in AML with KIT mutations.