Vertebrate lonesome kinase modulates the hepatocyte secretome to prevent perivascular liver fibrosis and inflammation.
Pkdcc
Collagen
Fibrosis
Liver
Secreted kinase
VLK
Journal
Journal of cell science
ISSN: 1477-9137
Titre abrégé: J Cell Sci
Pays: England
ID NLM: 0052457
Informations de publication
Date de publication:
01 04 2022
01 04 2022
Historique:
received:
12
08
2021
accepted:
08
03
2022
pubmed:
17
3
2022
medline:
14
4
2022
entrez:
16
3
2022
Statut:
ppublish
Résumé
Vertebrate lonesome kinase (VLK) is the only known extracellular tyrosine kinase, but its physiological functions are largely unknown. We show that VLK is highly expressed in hepatocytes of neonatal mice, but downregulated during adulthood. To determine the role of VLK in liver homeostasis and regeneration, we generated mice with a hepatocyte-specific knockout of the VLK gene (Pkdcc). Cultured progenitor cells established from primary hepatocytes of Pkdcc knockout mice produced a secretome, which promoted their own proliferation in 3D spheroids and proliferation of cultured fibroblasts. In vivo, Pkdcc knockout mice developed liver steatosis with signs of inflammation and perivascular fibrosis upon aging, combined with expansion of liver progenitor cells. In response to chronic CCl4-induced liver injury, the pattern of deposited collagen was significantly altered in these mice. The liver injury marker alpha-fetoprotein (AFP) was increased in the secretome of VLK-deficient cultured progenitor cells and in liver tissues of aged or CCl4-treated knockout mice. These results support a key role for VLK and extracellular protein phosphorylation in liver homeostasis and repair through paracrine control of liver cell function and regulation of appropriate collagen deposition. This article has an associated First Person interview with the first author of the paper.
Identifiants
pubmed: 35293576
pii: 275016
doi: 10.1242/jcs.259243
pmc: PMC9016620
pii:
doi:
Substances chimiques
Collagen
9007-34-5
Protein-Tyrosine Kinases
EC 2.7.10.1
Vlk protein, mouse
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : PZ00P3_161512
Organisme : ETH Zürich Foundation
ID : ETH-25 17-1
Organisme : Novartis Foundation for Medical-Biological Research
ID : 18B106
Organisme : Eidgenössische Technische Hochschule Zürich
ID : ETH-25 17-1
Organisme : Novartis Stiftung für Medizinisch-Biologische Forschung
ID : 18B106
Informations de copyright
© 2022. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
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