Related Experiment Video
Updated: Mar 30, 2026
11:19
Merging Absolute and Relative Quantitative PCR Data to Quantify STAT3 Splice Variant Transcripts
Published on: October 9, 2016
15.7K
Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity
Claudia Mertens1, Bhagwattie Haripal1, Sebastian Klinge2
1Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY 10065-6399;
Summary
Mutations in the STAT3 linker domain significantly inhibit its transcriptional activation. These findings reveal new targets for developing small molecules to inhibit persistently activated STAT3 in cancer.
Area of Science:
- Molecular Biology
- Structural Biology
- Cancer Research
Background:
- Signal transducer and activator of transcription (STAT) proteins play crucial roles in cellular signaling pathways.
- STAT3 is frequently and persistently activated in various human cancers, driving tumor growth and progression.
- Understanding the structural basis of STAT activation is key to developing targeted cancer therapies.
Purpose of the Study:
- To investigate the role of the STAT3 linker domain in transcriptional activation.
- To identify STAT3 linker domain mutants that inhibit STAT3 activity.
- To explore potential new therapeutic targets for small molecule-induced STAT3 inhibition in cancer.
Main Methods:
- Crystallography of phosphotyrosine-activated STAT1 and STAT1 dimers bound to DNA.
- Generation and analysis of various STAT3 linker domain mutants.
- Assessment of the effects of these mutants on STAT3 transcriptional activation.
Main Results:
- Several STAT3 linker domain mutants were found to profoundly inhibit STAT3 transcriptional activation.
- These results suggest a functional interaction between the STAT3 linker domain and both the DNA-binding and SH2 domains.
- Specific linker domain mutations disrupt STAT3 dimerization and DNA binding, leading to reduced transcriptional activity.
Conclusions:
- The STAT3 linker domain is critical for regulating STAT3 transcriptional activity through interactions with other domains.
- STAT3 linker domain mutants offer promising avenues for developing novel therapeutic strategies.
- Targeting these interactions could lead to effective small molecule inhibitors for STAT3-driven cancers.
Related Concept Videos
02:04Covalently Linked Protein Regulators
9.9K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
9.9K
02:04Covalently Linked Protein Regulators
2.1K
2.1K
01:20The JAK-STAT Signaling Pathway
13.9K
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
01:22Amplifying Signals via Enzymatic Cascade
19.2K
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...
19.2K
01:22PI3K/mTOR/AKT Signaling Pathway
6.3K
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...
6.3K
01:02Phosphorylation
55.6K
The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
55.6K