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Related Concept Videos

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Receptor Tyrosine Kinases01:26

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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...
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Related Experiment Video

Updated: Feb 20, 2026

Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia
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RYK is a GPNMB receptor that drives MASH.

Yue Xi1,2, Waner Zeng1,2, Jie Luo1,2

  • 1State Key Laboratory of Metabolism and Regulation in Complex Organisms, College of Life Sciences, Wuhan University, Wuhan, China.

Nature
|February 18, 2026
PubMed
Summary

Metabolic-dysfunction-associated steatohepatitis (MASH) progression is driven by glycoprotein non-metastatic melanoma protein B (GPNMB) ectodomain (G-ECD) binding to receptor tyrosine kinase (RYK). Targeting this GPNMB-RYK axis offers a promising therapeutic strategy for MASH.

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Area of Science:

  • Hepatology
  • Molecular Biology
  • Biochemistry

Background:

  • Metabolic-dysfunction-associated steatohepatitis (MASH) prevalence is increasing globally, with limited effective treatment options.
  • Glycoprotein non-metastatic melanoma protein B (GPNMB) is upregulated in MASH-protected mice.

Purpose of the Study:

  • To investigate the role of GPNMB in MASH pathogenesis.
  • To identify the receptor for GPNMB ectodomain (G-ECD) and elucidate the underlying molecular mechanisms.
  • To explore therapeutic strategies targeting the GPNMB-RYK axis for MASH treatment.

Main Methods:

  • Systemic or hepatocyte-specific Gpnmb ablation in diet-induced MASH mouse models.
  • Identification of G-ECD receptor using a cell-surface-displayed transmembrane protein library.
  • Hepatocyte-specific Ryk ablation and assessment of MASH progression.
  • Analysis of downstream signaling pathways including ERK1/2, PPARγ-CD36, and SREBP1C.
  • Evaluation of therapeutic interventions targeting the GPNMB-RYK axis.

Main Results:

  • GPNMB ablation protected against diet-induced MASH.
  • MASH progression was driven by the secreted GPNMB ectodomain (G-ECD), not full-length GPNMB.
  • Serum G-ECD levels correlated positively with MASH severity in human patients.
  • Receptor tyrosine kinase (RYK) was identified as the functional receptor for G-ECD.
  • Hepatocyte-specific Ryk ablation ameliorated MASH and blocked G-ECD's pathogenic effects.
  • G-ECD/RYK interaction activated ERK1/2 signaling, promoting hepatic lipid uptake and lipogenesis via PPARγ-CD36 and SREBP1C.
  • Therapeutic strategies targeting the GPNMB-RYK axis showed efficacy in preclinical MASH models.

Conclusions:

  • The GPNMB-RYK axis represents a novel ligand-receptor pathway implicated in MASH pathogenesis.
  • Targeting the GPNMB-RYK axis is a promising therapeutic strategy for treating MASH.