Related Experiment Video

Updated: May 25, 2026

Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System
08:15

Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System

Published on: April 11, 2025

IAPs limit activation of RIP kinases by TNF receptor 1 during development

Maryline Moulin1, Holly Anderton, Anne K Voss

  • 1La Trobe Institute for Molecular Science, La Trobe University, Victoria, Australia.

The EMBO Journal
|February 14, 2012
PubMed

Insights

Inhibitor of apoptosis proteins (IAPs) are crucial for embryonic development. Deleting specific IAP genes, like cIAP1 and cIAP2, causes embryonic lethality rescued by inhibiting TNF receptor 1 signaling.

Area of Science:

  • Cellular biology
  • Developmental biology
  • Immunology

Background:

  • Inhibitor of apoptosis (IAP) proteins, including cIAP1, cIAP2, and XIAP, play vital roles in regulating apoptosis and cytokine signaling.
  • The overlapping functions of these IAPs complicate the understanding of their individual contributions.

Purpose of the Study:

  • To elucidate the distinct roles of cIAP1, cIAP2, and XIAP in embryonic development by analyzing gene deletion phenotypes.
  • To investigate the involvement of TNF receptor signaling pathways in IAP-dependent developmental processes.

Main Methods:

  • Generation of genetically modified mice with single and combined deletions of cIAP1, cIAP2, and XIAP genes.
  • Analysis of embryonic lethality and developmental phenotypes in knockout mouse models.
  • Assessment of rescue effects by deleting components of the TNF receptor signaling pathway, including TNF receptor 1 (TNFR1), TNF receptor 2 (TNFR2), and receptor-interacting protein kinase 1 (RIPK1) and RIPK3.

Main Results:

  • Single gene deletions of IAPs did not result in overt phenotypes.
  • Combined deletion of cIAP1 and cIAP2, or cIAP1 and XIAP, led to mid-embryonic lethality.
  • Deletion of TNFR1, but not TNFR2, rescued the lethality of cIAP2(-/-)cIAP1(-/-) double mutants.
  • Hemizygosity for RIPK1 or deletion of RIPK3 significantly improved the survival of IAP-deficient embryos, particularly cIAP2(-/-)cIAP1(-/-) mutants.

Conclusions:

  • cIAP1 and cIAP2 are essential for embryonic development, with their absence leading to lethality mediated by TNF receptor 1 signaling.
  • RIP kinases, activated through the TNFR1 pathway, are critical effectors whose activity is normally suppressed by cIAPs during development.
  • These findings highlight a crucial role for cIAPs in limiting RIP kinase activity within the TNF receptor 1 pathway to ensure proper embryonic development.

More Related Videos

Development and Application of Rapamycin-regulated Tyrosine Phosphatases06:56

Development and Application of Rapamycin-regulated Tyrosine Phosphatases

Published on: September 6, 2024

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α11:27

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α

Published on: November 2, 2018

Related Concept Videos

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...
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...
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...
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
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 heterodimer of NF-κB...