Essential role of Gas6 for glomerular injury in nephrotoxic nephritis

Yanagita, Motoko; Ishimoto, Yoshikazu; Arai, Hidenori; Nagai, Kojiro; Ito, Tsuyoshi; Nakano, Toru; Salant, David J.; Fukatsu, Atsushi; Doi, Toshio; Kita, Toru

doi:10.1172/jci0214861

Cited by 79 publications

(85 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Each protein has a ~60 amino-acid Gla domain at its amino terminus, a region rich in glutamic 19 , genuine insights into the biological roles of these receptors were only obtained when mice lacking TYRO3, AXL, MER or GAS6 were generated and analysed [20][21][22][23][24][25] .…”

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

“…In contrast to most other receptor PTKs, expression of the TAMs is substantially upregulated postnatally, and is maintained at relatively high levels in adult tissues. Although cDNAs encoding the TAM receptors have been cloned repeatedly from tumour cells, and TAM receptors, particularly AXL, have been implicated in cancer progression 19 , genuine insights into the biological roles of these receptors were only obtained when mice lacking TYRO3, AXL, MER or GAS6 were generated and analysed [20][21][22][23][24][25] .…”

Section: Biological Roles Of Tam Signallingmentioning

confidence: 99%

See 1 more Smart Citation

Immunobiology of the TAM receptors

2008

View full text Add to dashboard Cite

Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

show abstract

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

Section: Biological Roles Of Tam Signallingmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

View full text Add to dashboard Cite

show abstract

“…Gas6 supports haematopoietic stem cell growth 6 and promotes fibroblast and endothelial cell survival. [7][8][9] Gas6/Axl signaling induces accumulation of mesangial cells in kidney fibrosis, 10,11 vascular smooth muscle cells in response to intimal vascular injury, 12 and cardiac fibroblasts 9 during the wound healing process. Thus, this pathway has been increasingly implicated in growth and survival processes during development, regeneration, and tissue repair.…”

mentioning

confidence: 99%

Induction of Gas6 protein in CCl₄-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells

et al. 2006

View full text Add to dashboard Cite

The protein product of the growth arrest-specific gene 6 (Gas6) is a secreted ligand for tyrosine kinase receptors, among which Axl is the most widely distributed and displays the highest affinity for Gas6. The Gas6/Axl signaling pathway has been increasingly implicated in growth and survival processes occurring during development and tissue repair. In liver, after an acute or chronic injury, repair involves macrophages and hepatic stellate cells (HSC) activated into myofibroblastic cells (HSC/MFB), which produce cytokines and matrix proteins. We investigated the expression and the role of Gas6 and its receptor Axl in liver repair. Three days after CCl 4 -induced liver injury in the rat, we detected the expression of Gas6 in ED1-positive macrophages as well as in desmin-positive HSC, which accumulated in injured areas. Axl, the high-affinity receptor for Gas6, was detected in macrophages, HSC, and HSC/MFB. In vitro, expression of ␥-carboxylated Gas6 was strongly induced in HSC along with their transformation into myofibroblasts, and it exerted an anti-apoptotic effect on both HSC and HSC/MFB mediated by the Axl/PI3-kinase/Akt pathway. In conclusion, Gas6 is a survival factor for these cells and we suggest

show abstract

“…Later studies showed Axl upregulation at sites of vascular injury, suggesting a role for this receptor in vascular remodeling (29). In the kidney, Gas6-Axl interactions are important for mesangial cell proliferation (43) and play a role in nephrotoxic glomerular injury (45) as well as diabetic nephropathy (32). Interestingly, one intracellular signaling pathway that mediates mesangial cell proliferation occurs through signal transducer and activator of tranduction 3 (STAT3) activation (44).…”

mentioning

confidence: 99%

Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells

Hasanbasic

Cuerquis²,

Varnum³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

130

125

View full text Add to dashboard Cite

Gas6 is a γ-carboxylated ligand for the receptor tyrosine kinase Axl. Gas6-Axl interactions can rescue endothelial cells from apoptosis, and this study examined the intracellular signaling mechanisms responsible for this phenomenon. Using flow cytometry, we first confirmed that Gas6 can abrogate apoptosis induced by serum starvation of primary cultures of human umbilical vein endothelial cells (HUVECs). This effect is mediated through phosphorylation of the serine-threonine kinase Akt, with maximal phosphorylation observed after 4 h of treatment with 100 ng/ml Gas6. Inhibition of Akt phosphorylation and abrogation of gas6-mediated survival of HUVECs by wortmannin implicated phosphatidylinositol 3-kinase as the mediator of Akt phosphorylation. Dominant negative Akt constructs largely abrogated the protective effect of Gas6 on HUVECs, underscoring the importance of Akt activation in Gas6-mediated survival. Several downstream regulators of this survival pathway were identified in HUVECs, namely, NF-κB as well as the antiapoptotic and proapoptotic proteins Bcl-2 and caspase 3, respectively. We showed that NF-κB is phosphorylated early after Gas6 treatment as evidenced by doublet formation on Western blotting. As well, the level of Bcl-2 protein increased, supporting the notion that the Bcl-2 antiapoptotic pathway is stimulated. The levels of expression of the caspase 3 activation products p12 and p20 decreased with Gas6 treatment, consistent with a reduction in proapoptotic caspase 3 activation. Taken together, these experiments provide new information about the mechanism underlying Gas6 protection from apoptosis in primary endothelial cell cultures.

show abstract

Essential role of Gas6 for glomerular injury in nephrotoxic nephritis

Cited by 79 publications

References 30 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Induction of Gas6 protein in CCl₄-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells

Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells

Contact Info

Product

Resources

About

Essential role of Gas6 for glomerular injury in nephrotoxic nephritis

Cited by 79 publications

References 30 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells

Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells

Contact Info

Product

Resources

About

Induction of Gas6 protein in CCl₄-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells