Related Experiment Video

Updated: Aug 15, 2026

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

Binding and phosphorylation of par-4 by akt is essential for cancer cell survival

Anindya Goswami1, Ravshan Burikhanov, Aurelie de Thonel

  • 1Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, USA.

Molecular Cell
|October 8, 2005
PubMed

Insights

The PI3K-Akt pathway promotes cancer cell survival by inhibiting apoptosis. Akt phosphorylates Par-4, preventing its pro-apoptotic function, which is crucial for PTEN-induced apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The Phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway is frequently activated in cancer, conferring resistance to apoptosis and promoting tumor growth.
  • Dysregulation of this pathway can occur through loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, increased growth factor signaling, or oncogene expression.
  • The precise molecular mechanisms by which Akt promotes cancer cell survival remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular interactions and mechanisms by which the PI3K-Akt pathway regulates apoptosis in cancer cells.
  • To investigate the role of the pro-apoptotic protein Par-4 in the context of PI3K-Akt pathway activation and its impact on cancer cell survival.

Main Methods:

  • Investigated the physical interaction between Akt and Par-4 using co-immunoprecipitation assays.
  • Determined the specific domain of Par-4 involved in Akt binding (leucine zipper domain).
  • Assessed the effect of Akt on Par-4 phosphorylation and its functional consequence on apoptosis induction.
  • Utilized pharmacological inhibitors (LY294002), RNA interference, and dominant-negative Akt to suppress Akt activation and function.
  • Examined the impact of inhibiting Par-4 expression on apoptosis induced by Akt inhibition.

Main Results:

  • Akt was found to physically bind to the pro-apoptotic protein Par-4 through its leucine zipper domain.
  • Akt phosphorylates Par-4, thereby inhibiting its pro-apoptotic activity and promoting cancer cell survival.
  • Suppression of Akt activation or function using various methods led to apoptosis in cancer cells.
  • Apoptosis induced by inhibiting the PI3K-Akt pathway was dependent on Par-4 expression, as its inhibition blocked the apoptotic effect.
  • Inhibition of other Akt substrates did not rescue the apoptosis induced by PI3K-Akt pathway inhibition, highlighting Par-4's unique role.

Conclusions:

  • Par-4 is a critical mediator of apoptosis induced by the inhibition of the PI3K-Akt pathway.
  • Akt inactivates Par-4 through phosphorylation, which is essential for promoting cancer cell survival.
  • Targeting the interaction or phosphorylation of Par-4 by Akt represents a potential therapeutic strategy for overcoming resistance to apoptosis in cancer.

More Related Videos

Cell-Based Drug Screening for Inhibitors of Autophagy Related 4B Cysteine Peptidase09:51

Cell-Based Drug Screening for Inhibitors of Autophagy Related 4B Cysteine Peptidase

Published on: June 30, 2023

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

Related Concept Videos

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 rapamycin-insensitive companion...
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...
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...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...