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Related Concept Videos

Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

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Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
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TGF - β Signaling Pathway01:16

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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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Receptor Downregulation in MVBs01:15

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Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
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GPCR Desensitization01:12

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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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GPCRs Regulate Adenylyl Cylase Activity01:09

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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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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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Related Experiment Video

Updated: Dec 2, 2025

Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
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Curtailing FGF19's mitogenicity by suppressing its receptor dimerization ability.

Jianlou Niu1, Jing Zhao1,2, Jiamin Wu1

  • 1School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035 Zhejiang, China.

Proceedings of the National Academy of Sciences of the United States of America
|November 4, 2020
PubMed
Summary

Fibroblast Growth Factor 19 (FGF19) analogs were engineered to reduce tumor risk while maintaining therapeutic benefits for diabetes and liver disease. These nonmitogenic variants show promise for safer FGF19-based treatments.

Keywords:
FGF19FGFR4 dimerizationmetabolic activitystructure-based drug designtumorigenic activity

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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
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Area of Science:

  • Biochemistry
  • Endocrinology
  • Hepatology

Background:

  • Fibroblast Growth Factor 19 (FGF19) regulates bile acid homeostasis and improves metabolic parameters.
  • FGF19 shows therapeutic potential for type 2 diabetes and liver diseases but carries a tumorigenic risk.
  • Mitogenic activity of FGF19 is linked to its receptor dimerization, a potential driver of adverse effects.

Purpose of the Study:

  • To engineer nonmitogenic FGF19 variants with retained therapeutic activities.
  • To reduce the tumorigenic potential of FGF19 for clinical applications.
  • To develop safer and more effective FGF19 analogs for metabolic and liver diseases.

Main Methods:

  • Engineered FGF19 variants with reduced binding affinity to FGFR and/or coreceptors (βklotho, heparan sulfate).
  • Assessed mitogenic activity of FGF19 variants.
  • Evaluated glycemic control and bile acid regulatory functions in WT and db/db mice.

Main Results:

  • Generated FGF19 variants (FGF19ΔFGFR, FGF19ΔKLB, FGF19ΔHBS) with significantly reduced mitogenic potential.
  • These variants maintained the glucose-lowering and bile acid-regulating efficacy of wild-type FGF19 (FGF19WT).
  • Pharmacological assays confirmed comparable metabolic benefits without increased mitogenicity.

Conclusions:

  • Nonmitogenic FGF19 variants can be developed by modulating FGFR dimerization.
  • Engineered FGF19 analogs retain beneficial metabolic and bile acid effects while losing mitogenic activity.
  • This strategy offers a pathway for developing safer FGF19-based therapeutics for diabetes and liver conditions.