Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6

Varnum, Brian; Young, Cynthia; Elliott, Gary; Garcia, Andy; Bartley, Timothy D.; Fridell, Yih-Woei C.; Hunt, R. W. G.; Trail, Geraldine; Clogston, Chris; Toso, Robert; Yanagihara, Donna L.; Bennett, L. G.; Sylber, Maura; Merewether, Lee Anne; Tseng, Alice; Escobar, Eva; Liu, Edison T.; Yamane, Harvey

doi:10.1038/373623a0

Cited by 441 publications

(371 citation statements)

References 12 publications

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“…Members of this family display IgG-like and fibronectin type III domains in their extracellular domain, features reminiscent of cell adhesion molecules; indeed, we were able to demonstrate that the ARK receptor can behave like a cell adhesion molecule by inducing cell aggregation through a homophelic mechanism (Bellosta et al, 1995). Recently Gas6 was identi®ed as a heterophilic ligand for ARK and Tyro3 receptors and c-mer, while Protein S was identi®ed as the ligand for the Tyro3 receptor (Nagata et al, 1996;Mark et al, 1996;Stitt et al, 1995;Varnum et al, 1995). Both proteins belong to the class of vitamin K dependent proteins but while Protein S is involved in the anticoagulation cascade (Dahlback, 1991), Gas6 was originally isolated as a Growth Arrest Speci®c gene from quiescent ®broblasts (Man®oletti et al, 1993).…”

Section: Introductionmentioning

confidence: 75%

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

et al. 1997

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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 e ect 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 signi®cant induction of DNA synthesis. Activation of ARK phosphorylation and a weak but signi®cant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. The antiapoptotic e ect of ARK signaling was con®rmed by studies using ®broblasts 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 TNFa 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.

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Section: Introductionmentioning

confidence: 75%

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

et al. 1997

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“…Recently, several studies have indicated that K vitamins are involved in processes other than blood coagulation and include growth control and differentiation (Akedo et al, 1992;Manfioletti et al, 1993;Stitt et al, 1995;Varnum et al, 1995;Crossier et al, 1996;Saxena et al, 1997;Yaguchi et al, 1997). These include:…”

Section: Initial Observations In Vitro and In Vivomentioning

confidence: 99%

“…(1) gas 6, the growth arrest-specific gene product, is carboxylated with vitamin K as a cofactor and binds to a growth-regulatory receptor, Axl (Varnum et al, 1995). (2) Two receptor tyrosine kinases (RTKs) involved in hematopoietic differentiation (Dkt and Ufo) employ vitamin K-carboxylated proteins as their ligands (Stitt et al, 1995;Crossier et al, 1996).…”

Section: Initial Observations In Vitro and In Vivomentioning

confidence: 99%

K vitamins, PTP antagonism, and cell growth arrest

Carr

Wang

Kar

2002

Journal Cellular Physiology

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The main function of K vitamins is to act as co-factors for g-glutamyl carboxylase. However, they have also recently been shown to inhibit cell growth. We have chemically synthesized a series of K vitamin analogs with various side chains at the 2 or 3 position of the core naphthoquinone structure. The analogs with short thio-ethanol side chains are found to be more potent growth inhibitors in vitro of various tumor cell lines. Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone] is one of the most potent. The anti-proliferation activity of these compounds is antagonized by exogenous thiols but not by non-thiol antioxidants. This suggests that the growth inhibition is mediated by sulfhydryl arylation of cellular glutathione and cysteine-containing proteins and not by oxidative stress. The protein tyrosine phosphatases (PTP) are an important group of proteins that contain cysteine at their catalytic site. PTPs regulate mitogenic signal transduction and cell cycle progression. PTP inhibition by Cpd 5 results in prolonged tyrosine phosphorylation and activation of several kinases and transcription factors including EGFR, ERK1/2, and Elk1. Cpd 5 could activate ERK1/2 either by signaling from an activated EGFR, which is upstream in the signaling cascade, or by direct inhibition of ERK1/2 phosphatase(s). Prolonged ERK1/2 phosphorylation strongly correlates with Cpd 5-mediated growth inhibition. Cpd 5 can also bind to and inhibit the Cdc25 family of dual specific phosphatases. As a result, several Cdc25 substrates (Cdk1, Cdk2, Cdk4) involved in cell cycle progression are tyrosine phosphorylated and thereby inhibited by its action. Cpd 5 could also inhibit both normal liver regeneration and hepatoma growth in vivo. DNA synthesis during rat liver regeneration following partial hepatectomy, transplantable rat hepatoma cell growth, and glutathione-S-transferase-pi expressing hepatocytes after administration of the chemical carcinogen diethylnitrosamine, are all inhibited by Cpd 5 administration. The growth inhibitory effect during liver regeneration and transplantable tumor growth is also correlated with ERK1/2 phosphorylation induced by Cpd 5. Thus, Cpd 5-mediated inhibition of PTPs, such as Cdc25 leads to cell growth arrest due to altered activity of key cellular kinases involved in signal transduction and cell cycle progression. This prototype K vitamin analog represents a novel class of growth inhibitor based upon its action as a selective PTP antagonist. It is clearly associated with prolonged ERK1/2 phosphorylation, which is in contrast with the transient ERK1/2 phosphorylation induced by growth stimulatory mitogens.

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“…AXL (also known as UFO/ARK/Tyro) is a RTK with oncogenic potential and transforming activity (Wimmel et al, 2001), which is stimulated by its ligand GAS6 (growth arrest-specific 6), a vitamin K-dependent growth potentiating factor (Varnum et al, 1995). AXL was first identified as a transforming gene in chronic myeloid leukemia (Janssen et al, 1991;O'Bryan et al, 1991), but is also overexpressed in metastatic colon and prostate cancer, thyroid carcinoma, breast cancer and melanoma (Quong et al, 1994;Craven et al, 1995;Ito et al, 1999;Jacob et al, 1999;Meric et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

AXL regulates mesothelioma proliferation and invasiveness

et al. 2010

Oncogene

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Mesothelioma is an asbestos-associated and notoriously chemotherapy-resistant neoplasm. Activation of the receptor tyrosine kinases (RTKs), epidermal growth factor receptor and MET, has been described in subsets of mesothelioma, suggesting that TKs might represent therapeutic targets in this highly lethal disease. We employed proteomic screening by phosphotyrosine immunoaffinity purification and tandem mass spectrometry to characterize RTK activation in mesothelioma cell lines. These assays demonstrated expression and activation of the AXL protein, which is an RTK with known oncogenic properties in non-mesothelial cancer types. AXL was expressed and activated strongly in 8 of 9 mesothelioma cell lines and 6 of 12 mesothelioma biopsies, including each of 12 mesotheliomas with spindle-cell histology. Somatic AXL mutations were not found, but all mesotheliomas expressed an alternatively spliced AXL transcript with in-frame deletion of exon 10, and six of seven mesothelioma cell lines expressed the AXL ligand, growth arrest-specific 6 (GAS6). GAS6 expression appeared to be functionally relevant, as indicated by modulation of AXL tyrosine phosphorylation by knockdown of endogeneous GAS6, and by administration of exogenous GAS6. AXL silencing by lentivirus-mediated short hairpin RNA suppressed mesothelioma migration and cellular proliferation due to G1 arrest. The AXL inhibitor DP-3975 inhibited cell migration and proliferation in mesotheliomas with strong AXL activation. DP-3975 response in these tumors was characterized by inhibition of PI3-K/AKT/mTOR and RAF/MAPK signaling. AXL inhibition suppressed mesothelioma anchorage-independent growth, with reduction in colony numbers and size. These studies suggest that AXL inhibitors warrant clinical evaluation in mesothelioma.

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Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6

Cited by 441 publications

References 12 publications

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

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

K vitamins, PTP antagonism, and cell growth arrest

AXL regulates mesothelioma proliferation and invasiveness

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