Related Experiment Video

Updated: Aug 8, 2026

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
08:47

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation

Published on: March 5, 2018

Caspase-mediated cleavage of the TIAM1 guanine nucleotide exchange factor during apoptosis

H Qi1, P Juo, J Masuda-Robens

  • 1University of Pennsylvania School of Medicine, Department of Cell and Developmental Biology, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.

Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research
|December 26, 2001
PubMed

Insights

During apoptosis, caspases cleave TIAM1, a Rac-specific guanine nucleotide exchange factor. This cleavage inactivates TIAM1 and Rac signaling, revealing a new regulatory mechanism in cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Rho family GTPases, including Rac and Cdc42, are key regulators of apoptosis.
  • The precise mechanisms controlling GTPase regulation during apoptosis are not fully understood.

Purpose of the Study:

  • To investigate how Rac-specific guanine nucleotide exchange factor TIAM1 is regulated during apoptosis.
  • To elucidate the functional consequences of TIAM1 cleavage in apoptotic signaling.

Main Methods:

  • Analysis of TIAM1 cleavage in various cell lines subjected to diverse apoptotic stimuli (ceramide, Fas, serum deprivation).
  • Biochemical assays to assess the guanine nucleotide exchange factor activity of TIAM1 cleavage products.
  • Examination of TIAM1's impact on downstream Rac effectors (c-Jun NH(2)-terminal kinase, serum response factor).

Main Results:

  • TIAM1 is cleaved by caspases at residue 993 during apoptosis across multiple cell types and stimuli.
  • Cleavage generates a stable fragment that lacks guanine nucleotide exchange factor activity for Rac.
  • The TIAM1 cleavage product fails to activate Rac and downstream signaling pathways, leading to Rac inactivation.

Conclusions:

  • Caspase-mediated cleavage of TIAM1 represents a novel mechanism for regulating guanine nucleotide exchange factor activity.
  • This cleavage inactivates Rac signaling pathways, contributing to the apoptotic process.
  • The findings provide new insights into the intricate molecular events governing cell death.

More Related Videos

Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches05:56

Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches

Published on: October 13, 2022

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry05:29

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry

Published on: March 24, 2023

Related Concept Videos

GTPases and their Regulation02:14

GTPases and their Regulation

Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
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.
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...
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...