Association of Cbl-Interacting Protein CIN85 with Protein Phosphatase 2A (PP2A) Partly Confer Neoplastic Properties to Human Leukemia Cell Lines
- 1Stem Cells and Regenerative Medicine, Blood and Cancer Research Department (BCR), King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
- 2Department of Biochemistry, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia
- 3Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11451, Saudi Arabia
Abstract
Protein phosphatase 2A (PP2A) is a critical tumor suppressor frequently inactivated in hematological malignancies, yet the mechanisms underlying this dysregulation remain poorly defined. Here, we investigated a novel interaction between the PP2A catalytic subunit (PP2Ac) and the adaptor protein CIN85. Analyzing transcriptomic datasets from AML, CML, CLL, and ALL patients, alongside functional validation in K562 and THP1 leukemia cell lines via RT-qPCR, immunoblotting, phosphatase activity assays, pharmacological modulation (FTY720 and Okadaic acid), siRNA-mediated knockdown, and proliferation assays, we found that CML and CLL exhibit reduced PP2A and elevated CIN85, with activated AKT, SRC, and GSK-3β levels. Pharmacological activation of PP2A reduced AKT and GSK-3β phosphorylation, while inhibition had opposing effects, confirming PP2A’s regulatory role. Crucially, CIN85 silencing markedly enhanced PP2A phosphatase activity without changing PP2Ac protein levels, leading to robust dephosphorylation of AKT, SRC, and GSK-3β and significantly suppressing leukemic cell proliferation. Collectively, these results identify CIN85 as a previously unrecognized endogenous negative regulator that directly suppresses PP2A function in leukemia. Importantly, disrupting the PP2Ac-CIN85 complex effectively restores PP2A tumor-suppressive activity, dampens oncogenic signaling, and inhibits growth, providing mechanistic clarity and positioning this protein-protein interface as one of the possible therapeutic targets for treating hematological cancers.
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BibTeX
@article{aldahami2026association,
title = {{Association of Cbl-Interacting Protein CIN85 with Protein Phosphatase 2A (PP2A) Partly Confer Neoplastic Properties to Human Leukemia Cell Lines}},
author = {Malak Abdullah Aldahami and Rawan Abdulrahman Alfrayh and Yasser Basmaeil and Haya Nasser Bin Kulayb and Sabiha Fatima and Bader Alahmari and Tanvir Khatlani},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15201897},
url = {https://www.mdpi.com/2073-4409/15/20/1897},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Association of Cbl-Interacting Protein CIN85 with Protein Phosphatase 2A (PP2A) Partly Confer Neoplastic Properties to Human Leukemia Cell Lines
AU - Malak Abdullah Aldahami
AU - Rawan Abdulrahman Alfrayh
AU - Yasser Basmaeil
AU - Haya Nasser Bin Kulayb
AU - Sabiha Fatima
AU - Bader Alahmari
AU - Tanvir Khatlani
PY - 2026
DA - 2026/10/19
JO - Cells
DO - 10.3390/cells15201897
UR - https://www.mdpi.com/2073-4409/15/20/1897
AB - Protein phosphatase 2A (PP2A) is a critical tumor suppressor frequently inactivated in hematological malignancies, yet the mechanisms underlying this dysregulation remain poorly defined. Here, we investigated a novel interaction between the PP2A catalytic subunit (PP2Ac) and the adaptor protein CIN85. Analyzing transcriptomic datasets from AML, CML, CLL, and ALL patients, alongside functional validation in K562 and THP1 leukemia cell lines via RT-qPCR, immunoblotting, phosphatase activity assays, pharmacological modulation (FTY720 and Okadaic acid), siRNA-mediated knockdown, and proliferation assays, we found that CML and CLL exhibit reduced PP2A and elevated CIN85, with activated AKT, SRC, and GSK-3β levels. Pharmacological activation of PP2A reduced AKT and GSK-3β phosphorylation, while inhibition had opposing effects, confirming PP2A’s regulatory role. Crucially, CIN85 silencing markedly enhanced PP2A phosphatase activity without changing PP2Ac protein levels, leading to robust dephosphorylation of AKT, SRC, and GSK-3β and significantly suppressing leukemic cell proliferation. Collectively, these results identify CIN85 as a previously unrecognized endogenous negative regulator that directly suppresses PP2A function in leukemia. Importantly, disrupting the PP2Ac-CIN85 complex effectively restores PP2A tumor-suppressive activity, dampens oncogenic signaling, and inhibits growth, providing mechanistic clarity and positioning this protein-protein interface as one of the possible therapeutic targets for treating hematological cancers.
SN - 2073-4409
ER -