Regulation and possible function of axl expression in immature human mast cells

Heide, I.; Sokoll, Andrea; Henz, Beate M.; Nagel, S. A.; Kreißig, K.; Grützkau, Andreas; Grabbe, Jürgen; Wittig, B.; Neubauer, Andreas

doi:10.1007/s002770050443

Cited by 14 publications

(11 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, GAS6 may act as a chemoattractant (19). Hematopoietic cells of all lineages express Axl (29,30), and GAS6 produced by stromal cells could induce chemotaxis of Axl-expressing progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic progenitor cells grow on 3T3 fibroblast monolayers that overexpress growth arrest-specific gene-6 (GAS6)

Dormady

Zhang

Basch

2000

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Pluripotential hematopoietic stem cells grow in close association with bone marrow stromal cells, which play a critical role in sustaining hematopoiesis in long-term bone marrow cultures. The mechanisms through which stromal cells act to support pluripotential hematopoietic stem cells are largely unknown. This study demonstrates that growth arrest-specific gene-6 (GAS6) plays an important role in this process. GAS6 is a ligand for the Axl (Ufo͞Ark), Sky (Dtk͞Tyro3͞Rse͞ Brt͞Tif), and Mer (Eyk) family of tyrosine kinase receptors and binds to these receptors via tandem G domains at its C terminus. After translation, GAS6 moves to the lumen of the endoplasmic reticulum, where it is extensively ␥-carboxylated. The carboxylation process is vitamin K dependent, and current evidence suggests that GAS6 must be ␥-carboxylated to bind and activate any of the cognate tyrosine kinase receptors. Here, we show that expression of GAS6 is highly correlated with the capacity of bone marrow stromal cells to support hematopoiesis in culture. Nonsupportive stromal cell lines express little to no GAS6, whereas supportive cell lines express high levels of GAS6. Transfection of the cDNA encoding GAS6 into 3T3 fibroblasts is sufficient to render this previously nonsupportive cell line capable of supporting long-term hematopoietic cultures. 3T3 cells, genetically engineered to stably express GAS6 (GAS6-3T3), produce a stromal layer that supports the generation of colony-forming units in culture (CFU-c) for up to 6 wk. Hematopoietic support by genetically engineered 3T3 is not vitamin K dependent, and soluble recombinant GAS6 does not substitute for coculturing the hematopoietic progenitors with genetically modified 3T3 cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Hematopoietic progenitor cells grow on 3T3 fibroblast monolayers that overexpress growth arrest-specific gene-6 (GAS6)

Dormady

Zhang

Basch

2000

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…33 Several studies suggest that Axl plays a role in differentiation of early myeloid progenitors, 33 thymic stromal cells, 34 and mast cells. 35 In addition, a triple knockout of all Axl-family receptors exhibited lymphoproliferative abnormalities attributable to increased expression of proinflammatory cytokines by activated macrophages. 7 Similarly, our data showed that decreased survival and/or differentiation of intimal macrophages and neutrophils resulted in a greater neutrophil recruitment to the LCA adventitia of Axl Ϫ/Ϫ mice ( Figure 5F).…”

Section: Discussionmentioning

confidence: 99%

Axl, A Receptor Tyrosine Kinase, Mediates Flow-Induced Vascular Remodeling

Korshunov

Mohan

Georger

et al. 2006

Circulation Research

102

View full text Add to dashboard Cite

Abstract-Intima-media thickening (IMT) in response to hemodynamic stress is a physiological process that requires coordinated signaling among endothelial, inflammatory, and vascular smooth muscle cells (VSMC). Axl, a receptor tyrosine kinase, whose ligand is Gas6, is highly induced in VSMC after carotid injury. Because Axl regulates cell migration, phagocytosis and apoptosis, we hypothesized that Axl would play a role in IMT. Vascular remodeling in mice deficient in Axl (Axl Ϫ/Ϫ ) and wild-type littermates (Axl ϩ/ϩ ) was induced by ligation of the left carotid artery (LCA) branches maintaining flow via the left occipital artery. Both genotypes had similar baseline hemodynamic parameters and carotid artery structure. Partial ligation altered blood flow equally in both genotypes: increased by 60% in the right carotid artery (RCA) and decreased by 80% in the LCA. There were no significant differences in RCA remodeling between genotypes. However, in the LCA Axl Ϫ/Ϫ developed significantly smaller intimaϩmedia compared with Axl Key Words: Axl Ⅲ flow Ⅲ carotid artery Ⅲ remodeling Ⅲ mouse Ⅲ apoptosis Ⅲ inflammation T he receptor tyrosine kinase Axl (also known as Ufo and Tyro7) belongs to a family of tyrosine receptors that includes Tyro3 (Sky) and Mer (Tyro12). 1,2 A common ligand for Axl family is Gas6 (Growth arrest-specific protein 6). 2,3 Important cellular functions of Gas6/Axl include cell adhesion, migration, phagocytosis, and inhibition of apoptosis. 4 -7 Gas6 and Axl family receptors are highly regulated in a tissue and disease specific manner. 8 -11 A recent genetic study found a significant association of a Gas6 mutation with stroke in humans. 12 Both Gas6 and Axl-family receptor knockout mice show abnormalities in platelet function, further supporting a vascular role for the Gas6/Axl pathway. 13,14 In human umbilical vein endothelial cells (HUVEC) and pulmonary artery EC, Gas6/Axl signaling promotes cell survival, 8,15 possibly via an autocrine pathway. 16 Gas6/Axlmediated survival signals include activation of Akt, phosphorylation of nuclear factor B (NF-B), increased expression of Bcl-2, and decreased caspase-3 activation. 17 Similarly, in vascular smooth muscle cells (VSMC), Gas6/Axl powerfully stimulates cell migration and cell survival. 18 We reported that Axl was highly regulated after rat carotid balloon injury consistent with a role in intimal VSMC proliferation. 19 Our recent findings showed that the Gas6/Axl/PI3K/Akt pathway inhibited VSMC apoptosis. 20 Moreover, Axl contributes to generation of reactive oxygen species in VSMC. 21 In addition, the Gas6/Axl pathway is important in the mammalian immune system. 7 Recent data suggest that the Axl family is a central regulator of macrophage activation and phagocytosis. 22 We developed a reproducible mouse model of flowdependent vascular remodeling that resembles human intimamedia thickening (IMT). 23 In response to decreased blood flow IMT occurs, which involves critical interactions among cells of the vessel wall. 23,24 Based on the significant rol...

show abstract

“…17 Autophosphorylation occurs through high-affinity interactions with Gas6, a secreted Gla-containing protein that shares significant amino acid homology with Protein S, a negative regulator of the coagulation cascade. 20,21 Axl has previously been detected in vitro in several cell types, including bone marrow stromal cells, 22 chondrocytes, 23 immature mast cells, 24 endothelial cells, 21,25,26 and vascular smooth muscle cells (VSMCs). 27 In vivo, Axl and Gas6 have been localized to articular cartilage, 23 rheumatoid arthritic synovium and synovial fluid, 28 and in the neointima of arteries after balloon injury.…”

Section: Discussionmentioning

confidence: 99%

Receptor Tyrosine Kinase Axl Modulates the Osteogenic Differentiation of Pericytes

Collett

Wood

Alexander

et al. 2003

Circulation Research

View full text Add to dashboard Cite

Abstract-Vascular pericytes undergo osteogenic differentiation in vivo and in vitro and may, therefore, be involved in diseases involving ectopic calcification and osteogenesis. The purpose of this study was to identify factors that inhibit the entry of pericytes into this differentiation pathway. RNA was prepared from pericytes at confluence and after their osteogenic differentiation (mineralized nodules). Subtractive hybridization was conducted on polyA PCR-amplified RNA to isolate genes expressed by confluent pericytes that were downregulated in the mineralized nodules. The subtraction product was used to screen a pericyte cDNA library and one of the positive genes identified was Axl, the receptor tyrosine kinase. Northern and Western blotting confirmed that Axl was expressed by confluent cells and was downregulated in mineralized nodules. Western blot analysis demonstrated that confluent pericytes also secrete the Axl ligand, Gas6. Immunoprecipitation of confluent cell lysates with an anti-phosphotyrosine antibody followed by Western blotting using an anti-Axl antibody, demonstrated that Axl was active in confluent pericytes and that its activity could not be further enhanced by incubating the cells with recombinant Gas6. The addition of recombinant Axl-extracellular domain (ECD) to pericyte cultures inhibited the phosphorylation of Axl by endogenous Gas6 and enhanced the rate of nodule mineralization. These effects were inhibited by coincubation of pericytes with Axl-ECD and recombinant Gas6.Together these results demonstrate that activation of Axl inhibits the osteogenic differentiation of vascular pericytes.

show abstract

Regulation and possible function of axl expression in immature human mast cells

Cited by 14 publications

References 27 publications

Hematopoietic progenitor cells grow on 3T3 fibroblast monolayers that overexpress growth arrest-specific gene-6 (GAS6)

Hematopoietic progenitor cells grow on 3T3 fibroblast monolayers that overexpress growth arrest-specific gene-6 (GAS6)

Axl, A Receptor Tyrosine Kinase, Mediates Flow-Induced Vascular Remodeling

Receptor Tyrosine Kinase Axl Modulates the Osteogenic Differentiation of Pericytes

Contact Info

Product

Resources

About