Vitamin K‐Dependent Actions of Gas6

Bellido-Martín, Lola; Frutos, Pablo García de

doi:10.1016/s0083-6729(07)00009-x

Cited by 65 publications

(48 citation statements)

References 141 publications

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“…Gas6 possesses a high structural homology and sequence identity to the natural anticoagulant protein S (ProS). However, Gas6 and ProS have clearly different biological roles [12,13]. …”

Section: Introductionmentioning

confidence: 99%

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Bárcena

Stefanović

Tutusaus

et al. 2015

Journal of Hepatology

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129

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Background & Aims Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase, and its ligand Gas6 are involved in cell differentiation, immune response and carcinogenesis. Methods HSCs were obtained from wild type and Axl−/− mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated wild type and Axl−/− mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. Results In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl KO mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. Conclusions: The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management.

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“…Gas6 possesses a high structural homology and sequence identity to the natural anticoagulant protein S (ProS). However, Gas6 and ProS have clearly different biological roles [12,13]. …”

Section: Introductionmentioning

confidence: 99%

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Bárcena

Stefanović

Tutusaus

et al. 2015

Journal of Hepatology

Self Cite

129

152

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“…Vitamin K-1 has a well-known role as a cofactor for gamma glutamyl carboxylase, GGCX, which carboxylates glutamine residues in vitamin K-dependent factors important in clotting (Merli and Fink, 2008;Shearer and Newman, 2008). Vitamin K also plays a role in bone health (Bugel, 2008), and acts as a cofactor for the GAS6 ligand for several receptor tyrosine kinases (Lamson and Plaza, 2003;Bellidomartin and Defrutos, 2008). Most relevant to TERE1 and tumor cell biology is that vitamin K-2, menaquinone, and vitamin K-3, also known as menadione, are redox-cycling and alkylating quinones known to inhibit growth of different types of tumor cell lines (Nishikawa et al, 1999;Lamson and Plaza, 2003;Jamison et al, 2004;Bandyopadhyay, 2008;Shearer and Newman, 2008;Amalia et al, 2010;Gilloteaux et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Fredericks

McGarvey

Wang

et al. 2011

DNA and Cell Biology

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Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression.

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“…For instance, Gas 6 antiapoptotic effects have been shown in VSMCs, endothelial cells, fibroblasts, and epithelial cells. 33 Furthermore, Gas 6 contributes to inflammatory processes, activates endothelial cells, promotes leukocyte and platelet endothelial sequestration, and participates in vasculitis induction. 8 To demonstrate a direct causal role of Gas 6 in Ald-induced pathology, we next selected Gas 6 Ϫ/Ϫ mice and subjected them to DOCA.…”

Section: Histopathologymentioning

confidence: 99%

Growth Arrest Specific Protein 6 Participates in DOCA-Induced Target-Organ Damage

et al. 2009

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Abstract-Growth arrest-specific protein 6 (Gas 6) is involved in inflammatory kidney diseases, vascular remodeling, cell adhesion, and thrombus formation. We explored a role for Gas 6 in aldosterone-induced target organ damage. We observed that Gas 6 was upregulated in rats with high aldosterone levels. Mineralocorticoid receptor blockade prevented target organ damage and decreased the elevated Gas 6 expression. Vascular smooth muscle cells given aldosterone increased their Gas 6 expression in vitro. To test the pathophysiological relevance, we investigated the effects of deoxycorticosterone acetate (DOCA) on Gas 6 gene-deleted ( Ϫ/Ϫ ) mice. After 6 weeks DOCA, Gas 6 Ϫ/Ϫ mice developed similar telemetric blood pressure elevations compared to wild-type mice but were protected from cardiac hypertrophy. Cardiac expression of interleukin 6 and collagen IV was blunted in Gas 6 Ϫ/Ϫ mice, indicating reduced inflammation and fibrosis. Gas 6 Ϫ/Ϫ mice also had an improved renal function with reduced albuminuria, compared to wild-type mice. Renal fibrosis and fibronectin deposition in the kidney were also reduced. Gas 6 deficiency reduces the detrimental effects of aldosterone on cardiac and renal remodeling independent of blood pressure reduction. Gas 6 appears to play a role in mineralocorticoid receptor-mediated target organ damage. Furthermore, because warfarin interferes with Gas 6 protein expression, the findings could be of clinical relevance for anticoagulant choices.

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Vitamin K‐Dependent Actions of Gas6

Cited by 65 publications

References 141 publications

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Growth Arrest Specific Protein 6 Participates in DOCA-Induced Target-Organ Damage

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