Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase

Keating, Amy K.; Salzberg, Dana; Sather, Susan; Liang, Xiayuan; Nickoloff, S; Anwar, Adil; DeRyckere, Deborah; Hill, Kimberley; Joung, David; Sawczyn, Kelly K.; Park, J; Curran‐Everett, Douglas; McGavran, Loris; Meltesen, Lynne; Gore, Lia; Johnson, Gary L.; Graham, Douglas K.

doi:10.1038/sj.onc.1209633

Cited by 87 publications

(78 citation statements)

References 47 publications

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“…In addition to the roles discussed in this Review, TAM receptor signalling has been shown have important regulatory roles in vascular smooth-muscle homeostasis [92][93][94] , in platelet function and thrombus stabilization 23,95,96 , in erythropoiesis 97 and in cancer development and progression 19,98,99 . TAM receptors are also implicated in the regulation of osteoclast function 100,101 , in the control of oligodendrocyte cell survival 102,103 , and in the infection of dendritic cells and other cells by Ebola and Marburg viruses 104,105 .…”

Section: Box 1 | Tam Receptor Signalling In Other Tissues and Organsmentioning

confidence: 99%

Section: Box 1 | Tam Receptor Signalling In Other Tissues and Organsmentioning

confidence: 99%

“…TAM receptors are also implicated in the regulation of osteoclast function 100,101 , in the control of oligodendrocyte cell survival 102,103 , and in the infection of dendritic cells and other cells by Ebola and Marburg viruses 104,105 . In many of these instances, the primary downstream TAM signalling pathway appears to be the phosphoinositide 3-kinase-AKT pathway 95,97,99,102,103 , rather than the Janus kinase-STAT (signal transducer and activator of transcription) pathway that is highlighted in this Review.Because knockout of each of the TAM genes still produced viable and fertile mice, and because the Tyro3 and Mer genes are linked in the mouse genome, it was possible to generate knockout mice that were deficient for all three TAM receptors 20 . Remarkably, even these triple knockout mice were found to be viable at birth, and to be superficially normal for the first several weeks thereafter.…”

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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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Section: Box 1 | Tam Receptor Signalling In Other Tissues and Organsmentioning

confidence: 99%

Section: Box 1 | Tam Receptor Signalling In Other Tissues and Organsmentioning

confidence: 99%

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Immunobiology of the TAM receptors

2008

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“…In addition to its role in the clearance of apoptotic cells, as demonstrated in MERTK knockout mice and in individuals with retinitis pigmentosa who display mutations in the MERTK gene, MERTK is overexpressed in several human cancers, including mantle cell lymphoma, gastric cancer, and T-cell acute lymphoblastic leukemia (53)(54)(55)(56). Despite the evidence from MERTK knockout mice and patients with retinitis pigmentosa that MERTK functions as an apoptotic cell removal receptor, in human cancers where MERTK is overexpressed, there appears to be suppressed apoptosis (55,57). MERTK may also have other functions, in that up-regulation of MERTK appears to lower the activation state of murine 32D myelomonocytic cells (58), and, when MERTK knockout mice are challenged with LPS, peritoneal macrophages up-regulate NF-kB and are susceptible to endotoxic shock through up-regulation of tumor necrosis factor-a (59).…”

Section: Expression Of Mertk On Amsmentioning

confidence: 99%

Overexpression of Apoptotic Cell Removal Receptor MERTK in Alveolar Macrophages of Cigarette Smokers

Kazeros

Harvey²,

Carolan³

et al. 2008

Am J Respir Cell Mol Biol

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Mononuclear phagocytes play an important role in the removal of apoptotic cells by expressing cell surface receptors that recognize and remove apoptotic cells. Based on the knowledge that cigarette smoking is associated with increased lung cell turnover, we hypothesized that alveolar macrophages (AMs) of normal cigarette smokers may exhibit enhanced expression of apoptotic cell removal receptor genes. AMs obtained by bronchoalveolar lavage of normal nonsmokers (n 5 11) and phenotypic normal smokers (n 5 13; 36 6 6 pack-years) were screened for mRNA expression of all known apoptotic cell removal receptors using Affymetrix HG-U133 Plus 2.0 microarray chips with TaqMan RT-PCR confirmation. Of the 14 known apoptotic receptors expressed, only MER tyrosine kinase (MERTK), a transmembrane tyrosine kinase receptor, was significantly up-regulated in smokers. MERTK expression was then assessed in AMs of smokers versus nonsmokers by TaqMan RT-PCR, immunocytochemistry, Western analysis, and flow analysis. Smoker AMs had up-regulation of MERTK mRNA levels (smoker vs. nonsmoker: 3.6-fold by microarray, P , 0.003; 9.5-fold by TaqMan RT-PCR, P , 0.02). Immunocytochemistry demonstrated a qualitative increase in MERTK protein expression on AMs of smokers. Increased protein expression of MERTK on AMs of smokers was confirmed by Western and flow analyses (P , 0.007 and P , 0.0002, respectively). MERTK, a cell surface receptor that recognizes apoptotic cells, is expressed on human AMs, and its expression is up-regulated in AMs of cigarette smokers. This up-regulation of MERTK may reflect an increased demand for removal of apoptotic cells in smokers, an observation with implications for the development of chronic obstructive pulmonary disease, a disorder associated with dysregulated apoptosis of lung parenchymal cells.Keywords: apoptosis; MER tyrosine kinase; alveolar macrophages MER receptor tyrosine kinase (MERTK), a 110-kD transmembrane protein member of the receptor tyrosine kinase family of cell surface receptors, plays a role in the clearance of apoptotic cells (1-4). The MERTK gene is normally expressed on mononuclear phagocytes, dendritic cells, retinal pigment epithelial (RPE) cells, and reproductive tissue (5-8). In mice, deletion of MERTK results in delayed clearance of apoptotic cells and development of autoimmune disease (1, 9, 10). In humans, mutations in MERTK result in retinitis pigmentosa, a disease characterized by a defect in the RPE phagocytosis pathway, where the RPE cells are unable to ingest the shed apoptotic tips of photoreceptor cells (11)(12)(13)(14).In the lung, the clearance of apoptotic cells is the normal function of alveolar macrophages (AMs), the monocyte-derived pulmonary representative of the mononuclear phagocyte system (15-18). Because phagocytosis of apoptotic cells by mononuclear phagocytes invokes an array of receptors on the phagocyte that interacts with bridging molecules and cell-specific ligands on the apoptotic cells, the control of expression of apoptotic receptors on the phagocyte plays ...

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“…TAM inhibits inflammation in macrophages and dendritic cells (Sharif et al, 2006;Rothlin et al, 2007), promotes the phagocytosis of apoptotic cells (Lu et al, 1999;Prasad et al, 2006) and stimulates the differentiation of natural killer cells (Caraux et al, 2006). In many of these instances, the primary downstream TAM signaling pathway appears to be PI3K/AKT pathway (Angelillo-Scherrer et al, 2001;Keating et al, 2006;Shankar et al, 2006); however, the Janus kinase-STAT pathway is essential for TAM-mediated immune responses (Rothlin et al, 2007). In addition, cooperative interaction between TAM receptor and cytokine receptor signaling network is required for many TAM-regulated biological functions (Budagian et al, 2005b;Rothlin et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis

Tan³

et al. 2009

Oncogene

257

271

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Dysregulation of Axl and its ligand growth arrest-specific 6 is implicated in the pathogenesis of several human cancers. In this study, we have used RNAi and monoclonal antibodies to assess further the oncogenic potential of Axl. Here we show that Axl knockdown reduces growth of lung and breast cancer xenograft tumors. Inhibition of Axl expression attenuates breast cancer cell migration and inhibits metastasis to the lung in an orthotopic model, providing the first in vivo evidence that links Axl directly to cancer metastasis. Axl knockdown in endothelial cells impaired tube formation and this effect was additive with anti-vascular endothelial growth factor (VEGF). Further analysis demonstrated that Axl regulates endothelial cell functions by modulation of signaling through angiopoietin/Tie2 and Dickkopf (DKK3) pathways. We have developed and characterized Axl monoclonal antibodies that attenuate non-small cell lung carcinoma xenograft growth by downregulation of receptor expression, reducing tumor cell proliferation and inducing apoptosis. Our data demonstrate that Axl plays multiple roles in tumorigenesis and that therapeutic antibodies against Axl may block Axl functions not only in malignant tumor cells but also in the tumor stroma. The additive effect of Axl inhibition with anti-VEGF suggests that blocking Axl function could be an effective approach for enhancing antiangiogenic therapy.

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Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase

Cited by 87 publications

References 47 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Overexpression of Apoptotic Cell Removal Receptor MERTK in Alveolar Macrophages of Cigarette Smokers

Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis

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