Related Experiment Video
Updated: Jun 12, 2026
07:49
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein
1Institute of Genetics and Biophysics 'A. Buzzati Traverso,' CNR, Naples, Italy.
Oncogene
|June 15, 2010
Summary
Fra-1 stabilizes c-Jun protein, a key component of activating protein-1 (AP-1) transcription complexes, by inhibiting its breakdown. This interaction is crucial for oncogenic RAS signaling, impacting cancer cell behavior.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Activating protein-1 (AP-1) transcription factors are crucial in tumorigenesis, with their stability influenced by various posttranslational modifications.
- The FOS family member Fra-1 is frequently overexpressed in cancers and regulates key oncogenic processes.
- Little is known about how AP-1 dimer composition affects the stability of its components, particularly c-Jun.
Purpose of the Study:
- To investigate the novel role of Fra-1 as a posttranslational regulator of c-Jun stability.
- To elucidate the mechanisms by which oncogenic RAS signaling influences c-Jun stability through Fra-1.
- To understand how heterodimerization with Fra-1 impacts c-Jun half-life.
Main Methods:
- Utilized constitutively and inducibly transformed rat thyroid cell lines.
- Investigated the role of the extracellular signal-related kinase (ERK) pathway.
- Analyzed the impact of c-Jun heterodimerization with Fra-1 on c-Jun protein stability.
Main Results:
- Oncogenic RAS expression leads to the stabilization of c-Jun.
- Fra-1 acts as a posttranslational regulator, stabilizing c-Jun.
- Fra-1-mediated c-Jun stabilization is dependent on ERK pathway activity and Fra-1 C-terminal domain phosphorylation.
- Heterodimerization with Fra-1 inhibits c-Jun degradation.
Conclusions:
- Fra-1 promotes c-Jun accumulation in response to oncogenic RAS signaling by inhibiting c-Jun breakdown.
- Fra-1 modulates AP-1 dimer composition and influences oncogenic signaling pathways.
- The phosphorylation of Fra-1's C-terminal domain is critical for stabilizing c-Jun in response to ERK signaling.
More Related Videos
Related Concept Videos
01:07MAPK 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...
01:19Interactions 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...
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...
01:22Amplifying 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...
01:25cAMP-dependent Protein Kinase Pathways
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
02:38The Ras Gene
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Ras is a superfamily...
01:26Receptor 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...