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PMID:15184064

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Citation

Stenhoff, J, Dahlbäck, B and Hafizi, S (2004) Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts. Biochem. Biophys. Res. Commun. 319:871-8

Abstract

The protein product of growth arrest specific gene 6 (Gas6), is the biological ligand for the Axl subfamily of receptor tyrosine kinases. We investigated the effects of exogenous Gas6 on growth of cardiac fibroblasts isolated from genetically Gas6-deficient mice. Recombinant Gas6, containing N terminal gamma-carboxyglutamic acid residues formed from a vitamin K-dependent reaction, stimulated both DNA synthesis and proliferation of cardiac fibroblasts under serum-free conditions. Gas6 also markedly enhanced survival of cells during prolonged serum starvation. Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase. The mitogenic effects of Gas6 were inhibited by neutralising anti-Gas6 antibodies and by a soluble Axl ectodomain fusion protein. In contrast, recombinant Gas6 from cells treated with warfarin, which prevents the gamma-carboxylation reaction, neither stimulated fibroblast proliferation nor activated Axl tyrosine phosphorylation. Gas6-induced cell proliferation was additive to the effects of epidermal growth factor, suggesting activation of discrete signalling pathways. In conclusion, Gas6 appears to be a unique growth factor for fibroblasts and post-translational gamma-carboxylation is necessary for its biological activity. These findings implicate vitamin K-dependent biochemical reactions in growth processes in development and in disease.

Links

PubMed Online version:10.1016/j.bbrc.2004.05.070

Keywords

Animals; Antibodies/metabolism; Cell Division/physiology; Culture Media, Serum-Free; Enzyme Activation; Fibroblasts/metabolism; Intercellular Signaling Peptides and Proteins/genetics; Intercellular Signaling Peptides and Proteins/metabolism; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases/metabolism; Myocardium/cytology; Oncogene Proteins/genetics; Oncogene Proteins/metabolism; Protein Processing, Post-Translational; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases/genetics; Receptor Protein-Tyrosine Kinases/metabolism; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Vitamin K/metabolism; Warfarin/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:GAS6

involved_in

GO:0048146: positive regulation of fibroblast proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GAS6

enables

GO:0048018: receptor ligand activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:GAS6

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GAS6

acts_upstream_of_or_within

GO:0007596: blood coagulation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2675495

P

Seeded From UniProt

complete

MOUSE:GAS6

acts_upstream_of_or_within

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2675495

P

  • regulates_o_occurs_in:(EMAPA:17331)
  • regulates_o_occurs_in:(CL:0000057)

Seeded From UniProt

complete


See also

References

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