Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Tsou, Wen I.; Nguyen, Khanh Q.; Calarese, D.A.; Garforth, S.; Antes, Anita; Smirnov, Sergey V.; Almo, S.C.; Birge, Raymond B.; Kotenko, Sergei V.

doi:10.1074/jbc.m114.569020

Cited by 187 publications

(215 citation statements)

References 56 publications

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“…However, the related TAM ligand PROS1 preferentially bound sTYRO3 and had much weaker binding to sAXL and sMERTK (Fig. 6C), in agreement with observations by Tsou et al (68) that PROS1 preferentially activates TYRO-3 and GAS6 favors AXL over the other TAM members. When testing the ability of soluble receptors to inhibit MERTK activation, we found that at the concentration of 0.1 M, sAXL effectively inhibited GAS6-induced MERTK phosphorylation while sMERTK could not (Fig.…”

Section: Resultssupporting

confidence: 81%

Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

Nguyen

Tsou

Calarese

et al. 2014

Journal of Biological Chemistry

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Background: Overexpression of MERTK tyrosine kinase is observed in many human cancers. Results: MERTK has a potent gain-of-function capacity to stimulate efferocytosis in epithelial cells. Conclusion: When overexpressed, MERTK acts as a preeminent efferocytosis receptor that is targetable by soluble Ig-domain containing TAM receptors. Significance: Our findings provide new mechanistic insight into how MERTK may impinge on tumor progression by enhancing efferocytosis.

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Section: Resultssupporting

confidence: 81%

Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

Nguyen

Tsou

Calarese

et al. 2014

Journal of Biological Chemistry

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“…Merdependent intrinsic chemoresistance 12 may be fundamentally different from coculture-driven Mer upregulation as the formation of complexes between TAM receptor ligands with apoptotic cells can cause an enhancement of Mer signaling. 33 Moreover, it has been shown that Mer is important for the ingestion of apoptotic cells by macrophages, partly by release of Gas6 and perpetuation of Mer activity. 41,42 This "niche"-dependent modulation of Mer may explain why Mer knockdown can result in MTX sensitization, 12 whereas in CNS cocultures, Mer inhibition reverses chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

“…on May 9, 2018. by guest www.bloodjournal.org From thereby enhancing receptor activation. 33 We therefore measured apoptotic cells in cocultures with leukemic cells and U343 or MSCs. For all cell lines, the number of apoptotic cells was higher in U343 than in MSC cocultures (supplemental Figure 2B).…”

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confidence: 99%

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

Krause¹,

Pfeiffer²,

Strube³

et al. 2015

Blood

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Key Points• Mer mediates quiescence and chemotherapy resistance in a CNS coculture model and causes CNS infiltration in immunodeficient mice.• Mer expression correlates with CNS positivity upon initial diagnosis in t(1;19)-positive pediatric ALL patients.Patients with t(1;19)-positive acute lymphoblastic leukemia (ALL) are prone to central nervous system (CNS) relapses, and expression of the TAM (Tyro3, Axl, and Mer) receptor Mer is upregulated in these leukemias. We examined the functional role of Mer in the CNS in preclinical models and performed correlative studies in 64 t(1;19)-positive and 93 control pediatric ALL patients. ALL cells were analyzed in coculture with human glioma cells and normal rat astrocytes: CNS coculture caused quiescence and protection from methotrexate toxicity in Mer high ALL cell lines, which was antagonized by short hairpin RNA-mediated knockdown of Mer. Mer expression was upregulated, prosurvival Akt and mitogen-activated protein kinase signaling were activated, and secretion of the Mer ligand Galectin-3 was stimulated. Mer high t(1;19) primary cells caused CNS involvement to a larger extent in murine xenografts than in their Mer low counterparts.Leukemic cells from Mer high xenografts showed enhanced survival in coculture.Treatment of Mer high patient cells with the Mer-specific inhibitor UNC-569 in vivo delayed leukemia onset, reduced CNS infiltration, and prolonged survival of mice. Finally, a correlation between high Mer expression and CNS positivity upon initial diagnosis was observed in t(1;19) patients. Our data provide evidence that Mer is associated with survival in the CNS in t(1;19)-positive ALL, suggesting a role as a diagnostic marker and therapeutic target. (Blood. 2015;125(5):820-830) Introduction TAM (Tyro3, Axl, and Mer) receptors have been advocated as therapeutic targets in human cancers including leukemia. 1-3 The TAM receptor family consists of Tyro3, Axl, and Mer 4 which all have been found to have transforming properties. [5][6][7] Mer expression has been shown on macrophages, natural killer (NK) cells, dendritic cells, megakaryocytes, and platelets, 8 but it is not known to be present on normal T and B lymphocytes at any stage of differentiation. Aberrant Mer expression was detected in not only acute myeloid leukemia (AML), 9 but also lymphocytic malignancies as T-cell acute lymphoblastic leukemia (T-ALL).10 Studies overexpressing Mer in fibroblasts found that it can induce extracellular signalregulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, nuclear factor-kB (NF-kB) and enhance cell survival via phosphatidylinositol 3-kinase (PI3K)/AKT. 2,11 Linger et al 12 reported that Mer is overexpressed on pre-B-cell ALL (B-ALL) cells of pediatric patients with t(1;19)(q23;p13) translocation. Furthermore, inhibition of Mer by RNA interference (RNAi) reduced survival and chemoresistance of pre-B-ALL cell lines and prolonged survival of xenografts.12 Pediatric ALL with t(1;19)(q23;p13) translocation is found in about 3% to 5% of ALL patients and has ...

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“…Macrophages were treated with 10 nM γ-carboxylated Gas6 for 1 h, which was added as conditioned medium harvested from Gas6-transfected HEK293-6E cells, as described (53). Conditioned medium from nontransfected HEK293 cells served as the control and is referred to in the figures as "vehicle."…”

Section: Methodsmentioning

confidence: 99%

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

Cai

Thorp

Doran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

178

201

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The acute inflammatory response requires a coordinated resolution program to prevent excessive inflammation, repair collateral damage, and restore tissue homeostasis, and failure of this response contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated in part by long-chain fatty acid-derived lipid mediators called specialized proresolving mediators (SPMs). However, how SPMs are regulated during the inflammatory response, and how this process goes awry in inflammatory diseases, are poorly understood. We now show that signaling through the Mer proto-oncogene tyrosine kinase (MerTK) receptor in cultured macrophages and in sterile inflammation in vivo promotes SPM biosynthesis by a mechanism involving an increase in the cytoplasmic:nuclear ratio of a key SPM biosynthetic enzyme, 5-lipoxygenase. This action of MerTK is linked to the resolution of sterile peritonitis and, after ischemia-reperfusion (I/R) injury, to increased circulating SPMs and decreased remote organ inflammation. MerTK is susceptible to ADAM metallopeptidase domain 17 (ADAM17)-mediated cellsurface cleavage under inflammatory conditions, but the functional significance is not known. We show here that SPM biosynthesis is increased and inflammation resolution is improved in a new mouse model in which endogenous MerTK was replaced with a genetically engineered variant that is cleavage-resistant (Mertk CR ). Mertk CR mice also have increased circulating levels of SPMs and less lung injury after I/R. Thus, MerTK cleavage during inflammation limits SPM biosynthesis and the resolution response. These findings contribute to our understanding of how SPM synthesis is regulated during the inflammatory response and suggest new therapeutic avenues to boost resolution in settings where defective resolution promotes disease progression.MerTK | efferocytosis | inflammation resolution | macrophages | 5-lipoxygenase

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Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Cited by 187 publications

References 56 publications

Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

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