Role of Gas6/Axl signaling in lens epithelial cell proliferation and survival.
Axl is a receptor tyrosine kinase that is activated by Gas6, a growth factor that belongs to the vitamin K-dependent protein family. Although Gas6 binding to Axl has been shown to transmit mitogenic and/or antiapoptotic signals to a variety of cell types, the role of the Axl-Gas6 system in normal and pathological lens biology is not known. We demonstrate for the first time that Axl protein is expressed in normal rat and bovine lens and that its ligand, Gas6, is present in bovine aqueous humor. In addition, we have detected tyrosine-phosphorylated Axl in normal rat and bovine lens epithelial tissues. We further show that human recombinant Gas6 is able to act as a growth factor in cultured human lens epithelial cells by activating Axl and then the AKT signaling pathway. Gas6 mediates a survival and anti-apoptotic response in cultured human lens epithelial cells subjected to serum-starvation (48-72hr), or treated with transforming growth factor beta1 (5 ng ml(-1), 48hr) or tumor necrosis alpha (100 ng ml(-1), 48hr), as demonstrated by increased number of viable cells, and decreased DNA condensation or caspase-3 activity. In contrast, Gas6 is not able to block apoptosis induced by staurosporin (1microM, 5-24hr) in human lens epithelial cells. Taken together, these data suggest that the Gas6/Axl signaling plays an important role in the control of lens epithelial cell growth and survival and hence in the maintenance of lens homeostasis.
Valverde
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JM USDA Human Nutrition Research Center on Aging at Tufts University, Boston MA 02111, USA. paloma.valverde@tufts.edu
Obin
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MS
Taylor
A
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001082:Aqueous Humor / Q000737:chemistry; D002417:Cattle; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005136:Eye Proteins / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*; D007908:Lens, Crystalline / Q000166:cytology* / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D005136:Eye Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6