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MER - human c-mer proto-oncogene tyrosine kinase

PDB entry: 2P0C

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Mer (C-mer, Mertk, Nyk, Axl2) is one of three human receptor tyrosine kinases with an extracellular domain architecture composed of dual immunoglobulin and fibronectin like domains recognizing a subset of hormone-like proteins including Growth Arrest Specific 6 [1]. In addition to being important in development, Mer is essential for phagocytosis, a biological role that defines macrophages and retinal pigment epithelial cells. Indeed, mutations in Mer cause retinitis pigmentosa [2;3]. Genetic knockout of Mer leads to impaired clearance of apoptotic thymocytes [4].

Mer and its paralogs have also been implicated in transformation, antiapoptosis, and cancer [5-7]. Experimental and clinical studies reveal elevated expression and activity in the following tumor tissues and tumor cell lines: ACTH-secreting adenomas [8], mantle cell lymphomas [9], T-cell acute lymphoblastic leukemia [10;11]. A better understanding of the molecular functions this class of RTK’s could lead to more effective anti-cancer therapies.

We have determined the first structure of the intracellular tyrosine kinase domain of this subclass of receptor tyrosine kinases. Unphosphorylated Mer in complex with AMP-PNP was crystallized and refined to 2.4 Å (PDB: 2P0C). The amino- and carboxy- terminal lobes adopt an unusual orientation relative to each other. In addition to the activation loop, other structural elements in the amino-terminal lobe that may interact with substrate peptides are flexible.

References

  1. S. Hafizi, B. Dahlback, Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily. FEBS J. 273 (2006) 5231-5244.
  2. P.M. D'Cruz, D. Yasumura, J. Weir, M.T. Matthes, H. Abderrahim, M.M. LaVail, D. Vollrath, Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum.Mol.Genet. 9 (2000) 645-651.
  3. A. Gal, Y. Li, D.A. Thompson, J. Weir, U. Orth, S.G. Jacobson, E. Apfelstedt-Sylla, D. Vollrath, Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat.Genet. 26 (2000) 270-271.
  4. R.S. Scott, E.J. McMahon, S.M. Pop, E.A. Reap, R. Caricchio, P.L. Cohen, H.S. Earp, G.K. Matsushima, Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411 (2001) 207-211.
  5. R. Jia, H. Hanafusa, The proto-oncogene of v-eyk (v-ryk) is a novel receptor-type protein tyrosine kinase with extracellular Ig/GN-III domains. J.Biol.Chem. 269 (1994) 1839-1844.
  6. M.M. Georgescu, K.H. Kirsch, T. Shishido, C. Zong, H. Hanafusa, Biological effects of c-Mer receptor tyrosine kinase in hematopoietic cells depend on the Grb2 binding site in the receptor and activation of NF-kappaB. Mol.Cell Biol. 19 (1999) 1171-1181.
  7. L. Ling, H.J. Kung, Mitogenic signals and transforming potential of Nyk, a newly identified neural cell adhesion molecule-related receptor tyrosine kinase. Mol.Cell Biol. 15 (1995) 6582-6592.
  8. C.O. Evans, A.N. Young, M.R. Brown, D.J. Brat, J.S. Parks, A.S. Neish, N.M. Oyesiku, Novel patterns of gene expression in pituitary adenomas identified by complementary deoxyribonucleic acid microarrays and quantitative reverse transcription-polymerase chain reaction. J.Clin.Endocrinol.Metab 86 (2001) 3097-3107.
  9. S. Ek, C.M. Hogerkorp, M. Dictor, M. Ehinger, C.A. Borrebaeck, Mantle cell lymphomas express a distinct genetic signature affecting lymphocyte trafficking and growth regulation as compared with subpopulations of normal human B cells. Cancer Res. 62 (2002) 4398-4405.
  10. D.K. Graham, D.B. Salzberg, J. Kurtzberg, S. Sather, G.K. Matsushima, A.K. Keating, X. Liang, M.A. Lovell, S.A. Williams, T.L. Dawson, M.J. Schell, A.A. Anwar, H.R. Snodgrass, H.S. Earp, Ectopic expression of the proto-oncogene Mer in pediatric T-cell acute lymphoblastic leukemia. Clin.Cancer Res. 12 (2006) 2662-2669.
  11. A.K. Keating, D.B. Salzberg, S. Sather, X. Liang, S. Nickoloff, A. Anwar, D. Deryckere, K. Hill, D. Joung, K.K. Sawczyn, J. Park, D. Curran-Everett, L. McGavran, L. Meltesen, L. Gore, G.L. Johnson, D.K. Graham, Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase. Oncogene 25 (2006) 6092-6100.