Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation

Oncogene. 1997 Nov 13;15(20):2387-97. doi: 10.1038/sj.onc.1201419.

Abstract

ARK (AXL) is the prototype of a distinctive family of receptor tyrosine kinases which contain in their extracellular domains features reminiscent of cell adhesion molecules. ARK is capable of homophilic binding, which results in a degree of receptor activation, but can also be activated by a heterophilic ligand, Gas6, a member of the family of vitamin K dependent proteins that is preferentially expressed in quiescent cells. Since a number of tissues and cell lines express both ARK and Gas6, we studied the effect of endogenous and exogenous Gas6 on the phenotype of ARK expressing cells. Here we show that constitutive expression of Gas6 in an NIH3T3 cell line that does not spontaneously express this protein does not result in cell transformation or uncontrolled growth, but protects from apoptosis induced by serum deprivation. Recombinant exogenous Gas6 was also capable of protecting cells from apoptosis at concentrations that did not result in significant induction of DNA synthesis. Activation of ARK phosphorylation and a weak but significant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. The antiapoptotic effect of ARK signaling was confirmed by studies using fibroblasts from ARK knock-out mice, that showed that the absence of ARK resulted in higher levels of serum deprivation-induced apoptosis, that could not be rescued by the addition of Gas6. Interestingly ARK signaling protects from apoptosis induced by serum deprivation, myc overexpression, or by TNF alpha but not from u.v. irradiation or Staurosporine. These results suggest that a major function of Gas6-ARK signaling is that of increasing cell survival under conditions which do not allow cell proliferation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells / drug effects
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis / radiation effects
  • Axl Receptor Tyrosine Kinase
  • CHO Cells / drug effects
  • Cell Division / drug effects
  • Cricetinae
  • Culture Media, Serum-Free / pharmacology
  • DNA Replication / drug effects
  • Growth Substances / pharmacology*
  • Intercellular Signaling Peptides and Proteins*
  • Mice
  • Mice, Knockout
  • Oncogene Proteins*
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Proteins / physiology
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc / physiology
  • Receptor Protein-Tyrosine Kinases / drug effects
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Staurosporine / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ultraviolet Rays

Substances

  • Culture Media, Serum-Free
  • Growth Substances
  • Intercellular Signaling Peptides and Proteins
  • Oncogene Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • growth arrest-specific protein 6
  • Receptor Protein-Tyrosine Kinases
  • Staurosporine
  • Axl Receptor Tyrosine Kinase