The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases

Stitt, Trevor N.; Conn, Greg; Goret, Martin; Lai, Cary; Bruno, Joanne; Radzlejewski, Czeslaw; Mattsson, Karen; Fisher, John P.; Gies, David R.; Jones, Pamela F.; Masiakowski, Piotr; Ryan, Terence E.; Tobkes, N; Chen, D.H; DiStefano, Peter S.; Long, George L.; Basilico, Claudio; Goldfarb, Mitchell; Lemke, Greg; Glass, David J.; Yancopouloš, George D.

doi:10.1016/0092-8674(95)90520-0

Cited by 678 publications

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“…AXL (Greek word anexelekto or uncontrolled), a transforming gene, was isolated from patients with chronic myelogenous leukemia (CML) (O'Bryan et al, 1991) and is a member of a Ufo/AXL subfamily of RTKs that includes Mer/Nyk/ Eyk and Rse/Tyro3 (Chen et al, 1997). It is a multidomain glycoprotein (896 amino acids) and consists of an extracellular region (425 amino acids) composed of two immunoglobulin-like domains and two fibronectin type III domains, a transmembrane a-helical domain and a c-terminal tyrosine kinase domain (Stitt et al, 1995). AXL transduces signals from the ECM into the cytoplasm by binding to GAS-6 a g-carboxylated secreted protein that is sixfold overexpressed in GIST-R and is involved in the stimulation of cell proliferation by binding and activating AXL through an autocrine mechanism.…”

Section: Discussionmentioning

confidence: 99%

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

et al. 2007

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KIT or a-platelet-derived growth factor receptor (a-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IMsensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase -AXL -in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growtharrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.

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Section: Discussionmentioning

confidence: 99%

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

et al. 2007

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“…Although protein S was initially reported to be a specific agonist for TYRO3 (REF. 8 In this Review, we generally discuss GAS6 and protein S interchangeably. It is important to emphasize, however, that these proteins have different patterns of expression in mammalian tissues (Supplementary information S1 (table)) and different bioactivities.…”

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

“…When originally cloned, TYRO3, AXL and MER were orphans, in that their ligands were unknown and could not be predicted. A series of biochemical and cell-culture experiments identified two closely related proteins -growth-arrest-specific 6 (GAS6) and protein S -as TAM agonists 8 (FIG. 1).…”

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

“…Although protein S was initially reported to be a specific agonist for TYRO3 (REF. 8 ), more recent studies have demonstrated that in cells in which TYRO3 is co-expressed with MER, protein S is also a potent MER agonist 10 . An important issue with regard to published ligand-receptor interaction studies is that most have involved the assay of single agonists against single receptors.…”

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

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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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“…GAS6, a protein with sequence similarities to protein-S, was characterized as a ligand for Axl stimulating its tyrosine phosphorylation specifically. [11][12][13][14] Axl is most abundantly expressed in cells of mesenchymal origin, such as osteoblasts, fibroblasts, and blood cells. 15 With regard to hematopoietic tissues, the strongest expression was found in cells of monocytic origin.…”

Section: Introductionmentioning

confidence: 99%

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1999

Leukemia

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Receptor tyrosine kinases (RTK) play a significant role in the signal transduction of normal, and malignant hematopoietic cells. We have previously shown that Axl, a novel RTK, is mainly expressed in leukemias of myeloid origin, and that its expression may be associated with cells of monocytic origin. Since expression of certain RTKs in cancer may be associated with different biology and survival, we investigated whether the expression of Axl is associated with clinical characteristics and survival in acute myeloid leukemia (AML). RNA from 54 patients with AML treated in a cooperative group trial was analyzed in a retrospective and blinded manner using a semi-quantitative reverse transcriptase polymerase chain reaction-based assay with primers specific for the Axl gene. Axl expression was found in 19 out of the 54 cases (35%). Axl expression was not detected more frequently in patients of older age, specific FAB categories, or cases with extramedullary disease. However, there existed a correlation between Axl and bcl-2 expression levels. AML cells with high bcl-2 expression showed higher Axl expression (r = 0.32; P = 0.02), and furthermore, Axl transcript numbers were also higher in AML with high CD34 expression (n = 38, r = 0.42; P = 0.008). No significant difference between leukemias expressing and not expressing Axl was found with regard to complete remission rate. However, quantitative Axl expression was associated with worse progression-free and overall survival. Higher Axl levels had worse prognosis for progression-free (␤: 0.68, s.e.: 0.28, P = 0.015) and overall survival (␤: 0.61, s.e.: 0.31, P = 0.05) using multivariate Cox models adjusted for age, Auer rods and leukocyte counts. In conclusion, in this retrospective analysis, no difference with regard to clinical characteristics at diagnosis was found between AML patients whose leukemia cells show Axl expression vs patients whose cells are Axl negative. The association between Axl and bcl-2 and Axl and CD34 expression in de novo AML needs further investigation. Similarly, the negative impact of Axl levels on outcome should be confirmed in a larger cohort.

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The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases

Cited by 678 publications

References 29 publications

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

Immunobiology of the TAM receptors

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