Related Experiment Video

Updated: Jun 22, 2026

Strategies for Tracking Anastasis, A Cell Survival Phenomenon that Reverses Apoptosis
12:55

Strategies for Tracking Anastasis, A Cell Survival Phenomenon that Reverses Apoptosis

Published on: February 16, 2015

Akt and 14-3-3 control a PACS-2 homeostatic switch that integrates membrane traffic with TRAIL-induced apoptosis

Joseph E Aslan1, Huihong You, Danielle M Williamson

  • 1Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA.

Molecular Cell
|June 2, 2009
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in cancer cells is complex. Researchers found PACS-2, a protein, acts as a key TRAIL effector, with its phosphorylation state regulating cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising therapeutic agent for selectively eliminating diseased cells.
  • However, resistance to TRAIL in many cancer cells indicates a complex underlying apoptotic mechanism.

Purpose of the Study:

  • To identify key effectors mediating TRAIL-induced apoptosis.
  • To elucidate the regulatory mechanisms controlling PACS-2 function in TRAIL-mediated cell death.

Main Methods:

  • In vitro and in vivo studies using cancer cells and hepatocytes.
  • Pharmacologic and genetic manipulation of PACS-2 and Akt pathways.
  • Analysis of protein phosphorylation and interactions (PACS-2 Ser437, Akt, 14-3-3).

Main Results:

  • PACS-2 was identified as an essential effector for TRAIL-induced apoptosis in tumor cells and infected hepatocytes.
  • Akt phosphorylates PACS-2 at Ser437, and this phosphorylation, in conjunction with 14-3-3 binding, represses apoptosis and mediates membrane cargo trafficking.
  • TRAIL treatment induces dephosphorylation of PACS-2 Ser437, thereby activating its apoptotic function.

Conclusions:

  • The phosphorylation state of PACS-2 Ser437 acts as a molecular switch, integrating cellular homeostasis with TRAIL-induced apoptosis.
  • Targeting the PACS-2 phosphorylation pathway could overcome TRAIL resistance in cancer therapy.

More Related Videos

In Vivo Biosensor Tracks Non-apoptotic Caspase Activity in Drosophila13:21

In Vivo Biosensor Tracks Non-apoptotic Caspase Activity in Drosophila

Published on: November 27, 2016

Evaluation of Caspase Activation to Assess Innate Immune Cell Death10:23

Evaluation of Caspase Activation to Assess Innate Immune Cell Death

Published on: January 20, 2023

Related Concept Videos

The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Caspases01:24

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
Cellular Injury V: Apoptosis and Autophagy01:22

Cellular Injury V: Apoptosis and Autophagy

Cells respond to damage and stress through highly coordinated processes that decide whether they survive or undergo controlled self-destruction. Two major pathways involved in this regulation are apoptosis, a type of programmed cell death, and autophagy, a survival mechanism that helps cells adapt to adverse conditions.ApoptosisApoptosis removes aged or injured cells to maintain tissue balance. During this process, the cell shrinks, chromatin condenses and fragments, and membrane-bound...
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...
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.