Related Experiment Video

Updated: May 26, 2026

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors

Published on: July 17, 2020

TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2

Mireille Delhase1, Soo-Youl Kim, Ho Lee

  • 1Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. mdelhase@gmail.com

Proceedings of the National Academy of Sciences of the United States of America
|December 29, 2011
PubMed

Insights

TANK-binding kinase 1 (TBK1) promotes cell survival by activating the antiapoptotic protein plasminogen activator inhibitor-2 (PAI-2). PAI-2 stabilizes transglutaminase 2 (TG2), which inhibits caspase-3, preventing cell death.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Signal transduction pathways

Background:

  • Cell survival decisions upon TNF exposure depend on balancing pro- and antiapoptotic factors.
  • The antiapoptotic response to TNF involves transcription factors like NF-κB, regulated by IκB kinase (IKK) complex.
  • TANK-binding kinase 1 (TBK1) is a known survival promoter downstream of TNF, but its mechanism was unclear.

Purpose of the Study:

  • To elucidate the mechanism by which TBK1 promotes cell survival.
  • To identify downstream mediators of TBK1's antiapoptotic function.
  • To investigate the role of plasminogen activator inhibitor-2 (PAI-2) and transglutaminase 2 (TG2) in TBK1-mediated cell survival.

Main Methods:

  • Investigated TBK1's effect on RelA/p65 phosphorylation.
  • Assessed the induction of plasminogen activator inhibitor-2 (PAI-2) expression.
  • Examined the interaction between PAI-2 and transglutaminase 2 (TG2).
  • Utilized Tg2(-/-) mice to study TNF-dependent liver injury.

Main Results:

  • TBK1 triggers an antiapoptotic response through specific RelA/p65 phosphorylation.
  • TBK1-induced RelA phosphorylation leads to increased expression of antiapoptotic PAI-2.
  • PAI-2 limits caspase-3 activation by stabilizing TG2, which inactivates procaspase-3.
  • Tg2(-/-) mice exhibited increased susceptibility to TNF-induced liver injury.

Conclusions:

  • TBK1 activates an antiapoptotic pathway involving PAI-2 and TG2.
  • PAI-2 and TG2 are critical downstream mediators of TBK1's survival function.
  • This pathway plays a significant role in preventing TNF-dependent apoptotic cell death, particularly in liver injury models.

More Related Videos

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

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...
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...
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...
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...
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...