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

IF 4.1 2区医学 Q2 CELL BIOLOGY

Molecular Cancer Research Pub Date : 2024-01-02 DOI:10.1158/1541-7786.MCR-23-0115

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

{"title":"PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation.","authors":"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","doi":"10.1158/1541-7786.MCR-23-0115","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"94-103"},"PeriodicalIF":4.1000,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841656/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1541-7786.MCR-23-0115","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

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.

查看原文本刊更多论文

PRL2磷酸酶通过调节CBL磷酸化促进白血病细胞中致癌KIT信号传导。

受体酪氨酸激酶KIT在急性髓细胞白血病（AML）中经常被激活。虽然PRL2（PTP4A2）的高表达与AML中SCF/KIT信号的激活相关，但其潜在机制尚不完全清楚。我们发现PRL2的抑制显著降低了致癌KIT驱动的白血病的负担，并延长了白血病小鼠的生存期。PRL2增强白血病细胞中致癌KIT信号传导，促进其增殖和存活。我们发现PRL2在酪氨酸371处使CBL去磷酸化，并抑制其对KIT的活性，导致白血病细胞中KIT泛素化减少，AKT和ERK信号增强。启示：我们的研究揭示了一种新的机制，可以微调白血病细胞中的致癌KIT信号，并可能将PRL2确定为具有KIT突变的AML的新治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Molecular Cancer Research 医学-细胞生物学

CiteScore

9.90

自引率

0.00%

发文量

280

审稿时长

4-8 weeks

期刊介绍： Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.