Related Experiment Video

Updated: Apr 1, 2026

Using the E1A Minigene Tool to Study mRNA Splicing Changes
10:25

Using the E1A Minigene Tool to Study mRNA Splicing Changes

Published on: April 22, 2021

5.6K

Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of

Nicole M Martinez1, Laura Agosto1, Jinsong Qiu2

  • 1Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

Genes & Development
|October 8, 2015
PubMed

Insights

Jun kinase (JNK) signaling activates a feedback loop by promoting alternative splicing of MAP kinase kinase 7 (MKK7). This splicing enhances JNK pathway activity and is controlled by the RNA-binding protein CELF2 during T-cell activation.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Signaling

Background:

  • Alternative splicing of signaling molecules is common, but its functional impact is often unclear.
  • Understanding how alternative splicing regulates immune cell signaling pathways is crucial.

Purpose of the Study:

  • To investigate the functional consequences of alternative splicing in MAP kinase kinase 7 (MKK7) during T-cell activation.
  • To elucidate the role of Jun kinase (JNK) signaling in regulating MKK7 alternative splicing and its impact on JNK pathway activity.

Main Methods:

  • Analysis of MKK7 alternative splicing in response to T-cell activation.
  • Assessment of JNK pathway activity via c-Jun phosphorylation and TNF-α expression.
  • Investigation of the role of RNA-binding protein CELF2 in regulating MKK7 splicing.

Main Results:

  • T-cell activation favors an MKK7 isoform lacking exon 2, which restores a JNK-docking site.
  • Skipping of MKK7 exon 2 enhances JNK pathway activity, creating a positive feedback loop.
  • JNK signaling and CELF2 are critical for MKK7 exon 2 repression, influencing ∼25% of T-cell receptor-mediated splicing events.

Conclusions:

  • MKK7 alternative splicing is a JNK-dependent positive feedback mechanism that amplifies JNK signaling during T-cell activation.
  • The JNK-CELF2 axis plays a significant role in controlling alternative splicing in T-cells, propagating JNK signaling.
  • This study reveals a novel regulatory axis controlling immune cell signaling through alternative splicing.
Keywords:
CELF2JNKMKK7alternative splicingpositive feedback

More Related Videos

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity07:09

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Published on: January 7, 2019

8.1K
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

9.6K

Related Concept Videos

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...
9.2K
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...
13.9K
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...
10.3K
T Cell Activation and Clonal Selection01:22

T Cell Activation and Clonal Selection

T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
17.4K
NF-kB-dependent Signaling Pathway02:26

NF-kB-dependent Signaling Pathway

2.5K
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...
7.9K