Related Experiment Video

Updated: Aug 25, 2025

Merging Absolute and Relative Quantitative PCR Data to Quantify STAT3 Splice Variant Transcripts
11:19

Merging Absolute and Relative Quantitative PCR Data to Quantify STAT3 Splice Variant Transcripts

Published on: October 9, 2016

15.1K

Aberrant function of pathogenic STAT3 mutant proteins is linked to altered stability of monomers and homodimers

Moses M Kasembeli1, Efiyenia Kaparos1, Uddalak Bharadwaj1

  • 1Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX.

Blood
|October 14, 2022
PubMed

Insights

STAT3 mutations impact protein stability, affecting DNA binding and disease. SH2D mutations altering STAT3 stability are key drivers of immunodeficiency, malignancy, and autoimmunity.

Area of Science:

  • Molecular Biology
  • Genetics
  • Immunology

Background:

  • Signal transducer and activator of transcription 3 (STAT3) mutations in the DNA-binding domain (DBD) and Src-homology 2 domain (SH2D) are linked to rare immunodeficiency, malignancy, and autoimmune disorders.
  • The precise molecular mechanisms underlying STAT3 dysfunction due to these mutations remain incompletely understood.

Purpose of the Study:

  • To investigate how loss-of-function (LOF) and gain-of-function (GOF) STAT3 mutations in the DBD and SH2D influence STAT3 monomer and homodimer protein stability.
  • To assess the impact of these mutations on critical STAT3 activation events, including phosphotyrosine (pY) site recruitment, Y705 phosphorylation, dimerization, nuclear translocation, and DNA binding.

Main Methods:

  • Analysis of STAT3 monomer and homodimer protein stability for various DBD and SH2D mutants.
  • Assessment of STAT3 recruitment to phosphotyrosine sites on peptide hormone receptors.
  • Evaluation of tyrosine phosphorylation at Y705, dimerization, nuclear translocation, and DNA binding capabilities.

Main Results:

  • STAT3 DBD LOF mutants exhibited reduced DNA binding, while DBD GOF mutants showed enhanced DNA binding, with minimal impact on protein stability or other functions.
  • STAT3 SH2D LOF mutants displayed reduced monomer and homodimer stability, leading to impaired pY-peptide recruitment, phosphorylation, dimerization, nuclear localization, and DNA binding.
  • Cancer-associated STAT3 SH2D GOF mutants demonstrated increased homodimer stability and enhanced DNA binding.
  • A STAT3 SH2D inhibitor effectively suppressed proliferation driven by SH2D GOF mutants.

Conclusions:

  • STAT3 protein monomer and homodimer stability are crucial in the pathogenesis of diseases linked to SH2D LOF and GOF mutations.
  • Modulating STAT3 monomer and/or homodimer protein stability presents a potential therapeutic strategy for diseases associated with STAT3 mutations.

More Related Videos

Protein Purification-free Method of Binding Affinity Determination by Microscale Thermophoresis10:22

Protein Purification-free Method of Binding Affinity Determination by Microscale Thermophoresis

Published on: August 15, 2013

30.7K
Screening for Functional Non-coding Genetic Variants Using Electrophoretic Mobility Shift Assay EMSA and DNA-affinity Precipitation Assay DAPA11:35

Screening for Functional Non-coding Genetic Variants Using Electrophoretic Mobility Shift Assay EMSA and DNA-affinity Precipitation Assay DAPA

Published on: August 21, 2016

13.1K

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...
9.1K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
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...
3.8K
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

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....
6.9K
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...
6.4K
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...
8.7K