Identification of the Product of Growth Arrest-specific Gene 6 as a Common Ligand for Axl, Sky, and Mer Receptor Tyrosine Kinases

Nagata, Kyoko; Ohashi, Kazumasa; Nakano, Toru; Arita, Hitoshi; Zong, Chen; Hanafusa, Hidesaburô; Mizuno, Kensaku

doi:10.1074/jbc.271.47.30022

Cited by 468 publications

(367 citation statements)

References 29 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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“…1). GAS6 was found to bind and activate -that is, stimulate the tyrosine autophosphorylation of -all three receptors, albeit with markedly different affinities (AXL≥TYRO3≫MER) 9 . Although protein S was initially reported to be a specific agonist for TYRO3 (REF.…”

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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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...

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“…8 As MerTK has a low-binding affinity for these ligands, other unknown ligand(s) or conditions may be required for MerTK activation. 9 Full activation of MerTK requires the autophosphorylation of tyrosine residues 749, 753 and 754 within the kinase domain. 10 MerTK knockout mice are fertile and viable but gradually develop lupuslike autoimmune disease as well as retinal dystrophy because of reduced efficiency of apoptotic cell clearance.…”

Section: Introductionmentioning

confidence: 99%

Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme

et al. 2012

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The infiltration of glioma cells into adjacent tissue is one of the major obstacles in the therapeutic management of malignant brain tumours, in most cases precluding complete surgical resection. Consequently, malignant glioma patients almost invariably experience tumour recurrences. Within the brain, glioma cells migrate rapidly either amoeboidly or mesenchymally to invade surrounding structures, in dependence on the extracellular environment. In addition, radiotherapy, frequently applied as adjuvant therapeutic modality, may enhance tumour cell mobility. Here, we show that the receptor tyrosine kinase Mer (MerTK) is overexpressed in glioblastoma multiforme (GBM) and that this is accompanied with increased invasive potential. MerTK expression is maintained in primary GBM-derived tumour spheres under stem cell culture conditions but diminishes significantly in serum-containing cultures with concomitant downregulation of Nestin and Sox2. Depletion of MerTK disrupts the rounded morphology of glioma cells and decreases their invasive capacity. Furthermore, the expression and phosphorylation of myosin light chain 2 are strongly associated with MerTK activity, indicating that the effect of MerTK on glioma cell invasion is mediated by actomyosin contractility. Finally, DNA damage robustly triggers the upregulation and phosphorylation of MerTK, which protects cells from apoptosis. This effect is strongly impaired upon MerTK depletion or overexpression of an inactive MerTK mutant. Collectively, our data suggests that MerTK is a novel therapeutic target in the treatment of the malignant gliomas.

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Identification of the Product of Growth Arrest-specific Gene 6 as a Common Ligand for Axl, Sky, and Mer Receptor Tyrosine Kinases

Cited by 468 publications

References 29 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

Immunobiology of the TAM receptors

Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme

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