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Gene Review

Mertk  -  c-mer proto-oncogene tyrosine kinase

Mus musculus

Synonyms: Eyk, Mer, Nyk, Proto-oncogene c-Mer, Receptor tyrosine kinase MerTK, ...
 
 
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Disease relevance of Mertk

  • Furthermore, soluble Mer decreased platelet aggregation in vitro and prevented fatal collagen/epinephrine-induced thromboembolism in mice, suggesting a potential therapeutic use for soluble Mer in the treatment of clotting disorders [1].
  • Thus, Mer receptor tyrosine kinase signaling participates in a novel inhibitory pathway in macrophages important for regulating TNF-alpha secretion and attenuating endotoxic shock [2].
  • The similarity in phenotypes between the two rodent models suggests that an RPE phagocytic defect is a feature of all types of retinal degeneration caused by loss of function of Mer tyrosine kinase, perhaps including mutations in human MERTK [3].
  • These data suggest that Mer plays a cooperative role in leukemogenesis and may be an effective target for biologically based leukemia/lymphoma therapy.Oncogene (2006) 25, 6092-6100. doi:10.1038/sj.onc.1209633; published online 1 May 2006 [4].
  • Mer is not normally expressed in thymocytes or lymphocytes; however, ectopic Mer RNA transcript and protein expression is found in a subset of acute lymphoblastic leukemia cell lines and patient samples, suggesting a role in leukemogenesis [4].
 

High impact information on Mertk

 

Biological context of Mertk

  • To investigate the transcriptional regulation of gene expression in the testis, a approximately 1.5 kb fragment of the 5' flanking sequence of Mer was isolated [8].
  • An E2F binding site which down-regulates Mer transcription, as revealed by EMSA, deletion and mutation studies, was identified downstream in the proximity of the promoter [8].
  • The related Axl, Sky and Mer receptor tyrosine kinases (RTKs) are increasingly being implicated in a host of discrete cellular responses including cell survival, proliferation, migration and phagocytosis [9].
  • Thus the Mer chimera blocks apoptosis without stimulating growth and produces cytoskeletal alterations; this outcome is clearly separable from the proliferative signal produced by most receptor tyrosine kinases [10].
  • Interestingly, Gas6 or CDMer failed to stimulate p130(CAS) tyrosine phosphorylation or phagocytosis in beta5-deficient CS-1 cells or in mutant beta5DeltaC-expressing cells, suggesting that Mer is directionally and functionally linked to the integrin pathway [11].
 

Anatomical context of Mertk

 

Associations of Mertk with chemical compounds

  • Because Mer and alphavbeta5 integrin share PS-dependent recognition signals, we investigated their post-receptor signaling cascades following receptor activation [11].
  • Unlike similar (related) receptors, Mer interacted with Vav1 constitutively and independently of phosphotyrosine, yet the site of binding localized to the Vav1 SH2 domain [15].
  • An SH2 domain-dependent, phosphotyrosine-independent interaction between Vav1 and the Mer receptor tyrosine kinase: a mechanism for localizing guanine nucleotide-exchange factor action [15].
  • By placing 2 mutated hormone-binding domains of murine estrogen receptor (Mer) at both termini of the Cre, we show that the fusion protein is active only on administration of the synthetic estrogen antagonist 4-hydroxytamoxifen (4-OHT) without any background in the absence of the inducing agent [16].
  • Here, we present a novel concept that relies on tamoxifen-dependent regulation of E1A activity through functional linkage to the mutated hormone-binding domain of the murine estrogen receptor (Mer) [17].
 

Regulatory relationships of Mertk

 

Other interactions of Mertk

  • In the present study, postnatal expression of Axl and Rse in mouse testes decreased during maturation while expression of Mer increased age-dependently during testicular development [8].
  • Unlike other agonists that lead to a slow (4-8 days) ligand-dependent differentiation of 32D cells, the combined Mer and IL-3 signal resulted in differentiated morphology and growth cessation in the first 24 h [10].
  • Moreover, and in contrast to EGFR, Mer chimera activation induced adherence and cell flattening in the normally suspension-growing 32D cells [10].
  • A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock [2].
 

Analytical, diagnostic and therapeutic context of Mertk

References

  1. A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation. Sather, S., Kenyon, K.D., Lefkowitz, J.B., Liang, X., Varnum, B.C., Henson, P.M., Graham, D.K. Blood (2007) [Pubmed]
  2. A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. Camenisch, T.D., Koller, B.H., Earp, H.S., Matsushima, G.K. J. Immunol. (1999) [Pubmed]
  3. An RCS-like retinal dystrophy phenotype in mer knockout mice. Duncan, J.L., LaVail, M.M., Yasumura, D., Matthes, M.T., Yang, H., Trautmann, N., Chappelow, A.V., Feng, W., Earp, H.S., Matsushima, G.K., Vollrath, D. Invest. Ophthalmol. Vis. Sci. (2003) [Pubmed]
  4. Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase. Keating, A.K., Salzberg, D.B., Sather, S., Liang, X., Nickoloff, S., Anwar, A., Deryckere, D., Hill, K., Joung, D., Sawczyn, K.K., Park, J., Curran-Everett, D., McGavran, L., Meltesen, L., Gore, L., Johnson, G.L., Graham, D.K. Oncogene (2006) [Pubmed]
  5. Phagocytosis and clearance of apoptotic cells is mediated by MER. Scott, R.S., McMahon, E.J., Pop, S.M., Reap, E.A., Caricchio, R., Cohen, P.L., Earp, H.S., Matsushima, G.K. Nature (2001) [Pubmed]
  6. Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Lu, Q., Gore, M., Zhang, Q., Camenisch, T., Boast, S., Casagranda, F., Lai, C., Skinner, M.K., Klein, R., Matsushima, G.K., Earp, H.S., Goff, S.P., Lemke, G. Nature (1999) [Pubmed]
  7. Loss of synchronized retinal phagocytosis and age-related blindness in mice lacking alphavbeta5 integrin. Nandrot, E.F., Kim, Y., Brodie, S.E., Huang, X., Sheppard, D., Finnemann, S.C. J. Exp. Med. (2004) [Pubmed]
  8. The proximal cis-acting elements Sp1, Sp3 and E2F regulate mouse mer gene transcription in Sertoli cells. Wong, C.C., Lee, W.M. Eur. J. Biochem. (2002) [Pubmed]
  9. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Hafizi, S., Dahlbäck, B. Cytokine Growth Factor Rev. (2006) [Pubmed]
  10. Mer receptor tyrosine kinase signaling: prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation. Guttridge, K.L., Luft, J.C., Dawson, T.L., Kozlowska, E., Mahajan, N.P., Varnum, B., Earp, H.S. J. Biol. Chem. (2002) [Pubmed]
  11. A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. Wu, Y., Singh, S., Georgescu, M.M., Birge, R.B. J. Cell. Sci. (2005) [Pubmed]
  12. AAV-Mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis pigmentosa. Smith, A.J., Schlichtenbrede, F.C., Tschernutter, M., Bainbridge, J.W., Thrasher, A.J., Ali, R.R. Mol. Ther. (2003) [Pubmed]
  13. Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases. Caraux, A., Lu, Q., Fernandez, N., Riou, S., Di Santo, J.P., Raulet, D.H., Lemke, G., Roth, C. Nat. Immunol. (2006) [Pubmed]
  14. Soluble Axl is generated by ADAM10-dependent cleavage and associates with Gas6 in mouse serum. Budagian, V., Bulanova, E., Orinska, Z., Duitman, E., Brandt, K., Ludwig, A., Hartmann, D., Lemke, G., Saftig, P., Bulfone-Paus, S. Mol. Cell. Biol. (2005) [Pubmed]
  15. An SH2 domain-dependent, phosphotyrosine-independent interaction between Vav1 and the Mer receptor tyrosine kinase: a mechanism for localizing guanine nucleotide-exchange factor action. Mahajan, N.P., Earp, H.S. J. Biol. Chem. (2003) [Pubmed]
  16. A tamoxifen-inducible chimeric Cre recombinase specifically effective in the fetal and adult mouse liver. Tannour-Louet, M., Porteu, A., Vaulont, S., Kahn, A., Vasseur-Cognet, M. Hepatology (2002) [Pubmed]
  17. Tamoxifen-regulated adenoviral E1A chimeras for the control of tumor selective oncolytic adenovirus replication in vitro and in vivo. Sipo, I., Wang, X., Hurtado Picó, A., Suckau, L., Weger, S., Poller, W., Fechner, H. Gene Ther. (2006) [Pubmed]
  18. The receptor tyrosine kinase MerTK activates phospholipase C gamma2 during recognition of apoptotic thymocytes by murine macrophages. Todt, J.C., Hu, B., Curtis, J.L. J. Leukoc. Biol. (2004) [Pubmed]
  19. The growth arrest-specific gene product Gas6 promotes the survival of human oligodendrocytes via a phosphatidylinositol 3-kinase-dependent pathway. Shankar, S.L., O'Guin, K., Cammer, M., McMorris, F.A., Stitt, T.N., Basch, R.S., Varnum, B., Shafit-Zagardo, B. J. Neurosci. (2003) [Pubmed]
 
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