Related Experiment Video

Updated: Oct 30, 2025

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

18.2K

PPP2R4 dysfunction promotes KRAS-mutant lung adenocarcinoma development and mediates opposite responses to MEK and

Bob Meeusen1, Emanuela Elsa Cortesi2, Judit Domènech Omella1

  • 1Laboratory of Protein Phosphorylation & Proteomics, Dept. Cellular & Molecular Medicine, KU Leuven, B-3000, Leuven, Belgium; KU Leuven Cancer Institute (LKI), B-3000, Leuven, Belgium.

Cancer Letters
|July 3, 2021
PubMed

Insights

Loss of the Protein Phosphatase 2A (PP2A) activator PTPA (PPP2R4) worsens survival in KRAS-mutant lung cancer. This loss impacts tumor growth and response to kinase inhibitors like MEK and mTOR inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • KRAS-mutant lung adenocarcinomas (NSCLC) have poor prognoses.
  • Protein Phosphatase 2A (PP2A) is a tumor suppressor involved in KRAS signaling.
  • The PP2A activator PTPA (PPP2R4) is frequently altered in NSCLC.

Purpose of the Study:

  • Investigate the role of PTPA (PPP2R4) in KRAS-mutant NSCLC.
  • Determine the impact of PTPA alterations on patient survival and tumor behavior.
  • Explore the effect of PTPA loss on response to kinase inhibitors.

Main Methods:

  • Analysis of PPP2R4 genetic alterations and expression in NSCLC patient cohorts.
  • In vitro studies using A549 cells with reduced or mutant PPP2R4.
  • In vivo xenograft and genetically engineered mouse models (KrasG12D).
  • Kinase inhibitor screening (MEK and mTOR inhibitors).

Main Results:

  • Heterozygous loss and mutations in PPP2R4 are associated with poorer survival in KRAS-mutant lung adenocarcinoma patients.
  • Reduced PPP2R4 expression promotes anchorage-independent growth, xenograft growth, and elevates Ki67 and c-MYC levels.
  • Ppp2r4 deficiency accelerates KrasG12D-induced lung tumorigenesis in mice.
  • PPP2R4 depletion confers resistance to MEK inhibitors (selumetinib) but sensitizes to mTOR inhibitors (temsirolimus).

Conclusions:

  • Loss-of-function of PTPA (PPP2R4) is a clinically relevant event in KRAS-mutant NSCLC.
  • PTPA alterations influence tumor progression and affect therapeutic strategies involving kinase inhibitors.
  • Targeting PP2A signaling pathways may offer new therapeutic avenues for KRAS-mutant NSCLC.
Keywords:
KRASNSCLCPP2APPP2R4SelumetinibTemsirolimus

More Related Videos

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

6.3K
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

380

Related Concept Videos

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...
4.0K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
4.3K
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
6.6K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.8K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
6.7K
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