PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation-Reference-Cited by-同舟云学术

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

Published:2023-09-27 Issue:1 Volume:22 Page:94-103
ISSN:1541-7786
Container-title:Molecular Cancer Research
language:en
Short-container-title:

Author:

Chen Hongxia¹²³^ORCID,Bai Yunpeng⁴^ORCID,Kobayashi Michihiro⁵^ORCID,Xiao Shiyu²^ORCID,Barajas Sergio²⁵^ORCID,Cai Wenjie²⁵^ORCID,Chen Sisi⁵^ORCID,Miao Jinmin⁴^ORCID,Nguele Meke Frederick⁴^ORCID,Yao Chonghua⁵⁶^ORCID,Yang Yuxia⁵⁷^ORCID,Strube Katherine⁵^ORCID,Satchivi Odelia⁵^ORCID,Sun Jianmin⁸^ORCID,Rönnstrand Lars⁸^ORCID,Croop James M.⁵^ORCID,Boswell H. Scott⁹^ORCID,Jia Yuzhi¹⁰^ORCID,Liu Huiping¹⁰¹¹^ORCID,Li Loretta S.¹¹¹²^ORCID,Altman Jessica K.²¹¹^ORCID,Eklund Elizabeth A.²¹¹¹³^ORCID,Sukhanova Madina¹⁴^ORCID,Ji Peng¹¹¹⁴^ORCID,Tong Wei¹⁵^ORCID,Band Hamid¹⁶^ORCID,Huang Danny T.¹⁷^ORCID,Platanias Leonidas C.²¹¹¹³^ORCID,Zhang Zhong-Yin⁴^ORCID,Liu Yan²¹¹^ORCID

Affiliation:

1. 1Department of Hematology, Chongqing University Three Gorges Hospital, Chongqing, China.

2. 2Department of Medicine, Northwestern University, Chicago, Illinois.

3. 3School of Medicine, Chongqing University, Chongqing, China.

4. 4Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana.

5. 5Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.

6. 6Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, China.

7. 7Department of Medical Genetics, Peking University Health Science Center, Beijing, China.

8. 8Division of Translational Cancer Research and Lund Stem Cell Center, Lund University, Lund, Sweden.

9. 9Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.

10. 10Department of Pharmacology, Northwestern University, Chicago, Illinois.

11. 11Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois.

12. 12Department of Pediatrics, Northwestern University, Chicago, Illinois.

13. 13Department of Medicine, Jesse Brown VA Medical Center, Chicago, Illinois.

14. 14Department of Pathology, Northwestern University, Chicago, Illinois.

15. 15Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

16. 16Department of Genetics, University of Nebraska Medical Center, Omaha, Nebraska.

17. 17Cancer Research UK Beatson Institute and Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.

Abstract

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.

Funder

DOD Peer Reviewed Cancer Research Program

Congressionally Directed Medical Research Programs

NHLBI Division of Intramural Research

National Institute of Diabetes and Digestive and Kidney Diseases

National Institute on Aging

National Cancer Institute

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology,Molecular Biology

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