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Related Concept Videos

GPCR Desensitization01:12

GPCR Desensitization

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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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...
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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...
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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...
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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...
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Related Experiment Video

Updated: Jun 11, 2025

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Gal-3 blocks the binding between PD-1 and pembrolizumab.

Stinne Ravn Greisen1,2, Mia Bendix3, Morten Aagaard Nielsen4,2

  • 1Rheumatology, Aarhus University Hospital, Aarhus, Denmark srg@biomed.au.dk.

Journal for Immunotherapy of Cancer
|October 2, 2024
PubMed
Summary

Galectin-3 blocks pembrolizumab binding to PD-1, hindering immune response in metastatic melanoma. High galectin-3 in tumors correlates with progression, while high plasma levels indicate longer survival, suggesting complex roles in treatment response.

Keywords:
BiomarkerImmune Checkpoint InhibitorsImmunotherapySkin Cancer

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A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
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Area of Science:

  • Immunology
  • Oncology
  • Biochemistry

Background:

  • Immune checkpoint inhibitors (ICI) have improved metastatic malignant melanoma (MM) survival.
  • Predictive biomarkers for ICI response are crucial due to treatment resistance in some patients.
  • Galectin-3 (Gal-3) is a potential biomarker and therapeutic target for ICI therapy.

Purpose of the Study:

  • Investigate the interaction between programmed cell death 1 (PD-1), pembrolizumab, and Gal-3 in metastatic MM.
  • Determine if Gal-3 influences pembrolizumab efficacy.
  • Explore Gal-3 as a predictive biomarker for ICI treatment response.

Main Methods:

  • Surface plasmon resonance (SPR) and cryogenic electron microscopy (cryo-EM) to visualize binding interactions.
  • In vitro T cell cultures to assess cytokine production.
  • Measurement of soluble PD-1 and Gal-3 levels in metastatic MM patients treated with pembrolizumab.

Main Results:

  • Gal-3 was shown to block PD-1 and pembrolizumab binding via steric inhibition.
  • Gal-3 reduced T cell pro-inflammatory cytokine production, unaffected by pembrolizumab.
  • High tumor Gal-3 correlated with disease progression, while high plasma Gal-3 correlated with longer progression-free survival.
  • Soluble PD-1 levels increased post-pembrolizumab treatment and correlated with disease progression.

Conclusions:

  • The interaction between PD-1 and Gal-3 interferes with pembrolizumab binding.
  • Gal-3-induced immune suppression in the tumor microenvironment is not overcome by pembrolizumab.
  • Gal-3 exhibits differential roles in plasma and tumor tissue regarding ICI treatment outcomes.