Related Experiment Video

Updated: Oct 18, 2025

Subcellular Fractionation of Primary Chronic Lymphocytic Leukemia Cells to Monitor Nuclear/Cytoplasmic Protein Trafficking
11:39

Subcellular Fractionation of Primary Chronic Lymphocytic Leukemia Cells to Monitor Nuclear/Cytoplasmic Protein Trafficking

Published on: October 23, 2019

11.7K

The PKN1- TRAF1 signaling axis as a potential new target for chronic lymphocytic leukemia

Maria I Edilova1, Jaclyn C Law1, Safoura Zangiabadi2

  • 1Department of Immunology, University of Toronto, Toronto, ON, Canada.

Oncoimmunology
|September 30, 2021
PubMed

Insights

The protein kinase N1 (PKN1) pathway protects TRAF1 in chronic lymphocytic leukemia (CLL). Inhibiting PKN1 with OTSSP167 reduces TRAF1 and induces CLL cell death, suggesting a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Signal Transduction

Background:

  • TRAF1 is a pro-survival protein overexpressed in B cell cancers like chronic lymphocytic leukemia (CLL).
  • The role of TRAF1 in human cancer and its regulation remain underexplored.
  • Constitutive CD40 signaling in lymphoma involves TRAF1, but its protective mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the role of protein kinase N1 (PKN1) in regulating TRAF1 stability.
  • To identify PKN1 inhibitors and evaluate their efficacy in CLL models.
  • To explore the PKN1-TRAF1 signaling axis as a potential therapeutic target in CLL.

Main Methods:

  • Assessed PKN1 expression in CLL patient samples.
  • Screened kinase inhibitors to identify PKN1 inhibitors.
  • Treated CLL cells and RAJI cells with identified inhibitors (OTSSP167, XL-228).
  • Analyzed protein levels (TRAF1, pNF-κB p65, pS6, pERK, Mcl-1, Bcl-2, cleaved caspase-3) and assessed drug synergy.

Main Results:

  • Active phospho-Thr774 PKN1 is constitutively expressed in CLL but not in healthy B cells.
  • PKN1 inhibition by OTSSP167 or XL-228 reduced TRAF1 levels in RAJI cells.
  • Treatment of primary CLL samples with OTSSP167 or XL-228 decreased TRAF1, Mcl-1, Bcl-2, and signaling proteins, while increasing cleaved caspase-3.
  • OTSSP167 synergized with venetoclax to induce CLL cell death.

Conclusions:

  • PKN1 protects TRAF1 from degradation during CD40 signaling, and this axis is active in CLL.
  • PKN1 inhibitors like OTSSP167 effectively reduce TRAF1 and induce apoptosis in CLL cells.
  • The PKN1-TRAF1 pathway represents a promising new therapeutic target for CLL, with OTSSP167 a potential combination therapy with venetoclax.
Keywords:
Chronic lymphocytic leukemiaTNFR-associated factors (TRAFS)protein kinase N1

More Related Videos

A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia09:52

A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia

Published on: December 4, 2018

7.7K
Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

352

Related Concept Videos

Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
80.8K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.7K
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
7.9K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
9.6K
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
3.2K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K