Ectodomain structures of Eph receptors

Seminars in Cell and Developmental Biology

Volumn 23, Issue 1, 2012, Pages 35-42

  Himanen, Juha P ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

Eph receptors; Ephrins; Receptor tyrosine kinase; Signaling; Subclass specificity

Indexed keywords

DIMER; EPHRIN; EPHRIN A1; EPHRIN A2; EPHRIN B1; EPHRIN B2; EPHRIN RECEPTOR; LIGAND;

CELL MEMBRANE; CLUSTER ANALYSIS; CRYSTAL STRUCTURE; DIMERIZATION; HUMAN; HYDROPHOBICITY; INFORMATION; NEOPLASM; NONHUMAN; PROTEIN DOMAIN; PROTEIN STRUCTURE; RECEPTOR BINDING; REVIEW;

EID: 84857443065     PISSN: 10849521     EISSN: 10963634     Source Type: Journal    
DOI: 10.1016/j.semcdb.2011.10.025     Document Type: Review

References (85)

1. Himanen J.P., Nikolov D.B. Eph signaling: a structural view. Trends Neurosci 2003, 26:46-51.
2. Klein R. Excitatory Eph receptors and adhesive ephrin ligands. Curr Opin Cell Biol 2001, 13:196-203.
3. Egea J., Klein R. Bidirectional Eph-ephrin signaling during axon guidance. Trends Cell Biol 2007, 17:230-238.
4. Flanagan J.G., Vanderhaeghen P. The ephrins and Eph receptors in neural development. Annu Rev Neurosci 1998, 21:309-345.
5. Genander M., Holmberg J., Frisen J. Ephrins negatively regulate cell proliferation in the epidermis and hair follicle. Stem Cells 2010, 28:1196-1205.
6. Genander M., Frisen J. Ephrins and Eph receptors in stem cells and cancer. Curr Opin Cell Biol 2010, 22:611-616.
7. Matsuo K. Eph and ephrin interactions in bone. Adv Exp Med Biol 2010, 658:95-103.
8. Murai K.K., Pasquale E.B. Can Eph receptors stimulate the mind?. Neuron 2002, 33:159-162.
9. Rodenas-Ruano A., Perez-Pinzon M.A., Green E.J., Henkemeyer M., Liebl D.J. Distinct roles for ephrinB3 in the formation and function of hippocampal synapses. Dev Biol 2006, 292:34-45.
10. Bouzioukh F., Wilkinson G.A., Adelmann G., Frotscher M., Stein V., Klein R. Tyrosine phosphorylation sites in ephrinB2 are required for hippocampal long-term potentiation but not long-term depression. J Neurosci 2007, 27:11279-11288.
11. Savelieva K.V., Rajan I., Baker K.B., Vogel P., Jarman W., Allen M., et al. Learning and memory impairment in Eph receptor A6 knockout mice. Neurosci Lett 2008, 438:205-209.
12. Simon A.M., de Maturana R.L., Ricobaraza A., Escribano L., Schiapparelli L., Cuadrado-Tejedor M., et al. Early changes in hippocampal Eph receptors precede the onset of memory decline in mouse models of Alzheimer's disease. J Alzheimers Dis 2009, 17:773-786.
13. Wu J., Luo H. Recent advances on T-cell regulation by receptor tyrosine kinases. Curr Opin Hematol 2005, 12:292-297.
14. Lackmann M., Mann R.J., Kravets L., Smith F.M., Bucci T.A., Maxwell K.F., et al. Ligand for EPH-related kinase (LERK) 7 is the preferred high affinity ligand for the HEK receptor. J Biol Chem 1997, 272:16521-16530.
15. Pasquale E.B. Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol 2005, 6:462-475.
16. Cowan C.A., Henkemeyer M. The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 2001, 413:174-179.
17. Marler K.J., Becker-Barroso E., Martinez A., Llovera M., Wentzel C., Poopalasundaram S., et al. A TrkB/ephrinA interaction controls retinal axon branching and synaptogenesis. J Neurosci 2008, 28:12700-12712.
18. Lim Y.S., McLaughlin T., Sung T.C., Santiago A., Lee K.F., O'Leary D.D. p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping. Neuron 2008, 59:746-758.
19. Adams R.H., Klein R. Eph receptors and ephrin ligands essential mediators of vascular development. Trends Cardiovasc Med 2000, 10:183-188.
20. Dodelet V.C., Pasquale E.B. Eph receptors and ephrin ligands: embryogenesis to tumorigenesis. Oncogene 2000, 19:5614-5619.
21. Vaught D., Brantley-Sieders D.M., Chen J. Eph receptors in breast cancer: roles in tumor promotion and tumor suppression. Breast Cancer Res 2008, 10:217.
22. Sjoblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006, 314:268-274.
23. Smith L.M., Walsh P.T., Rudiger T., Cotter T.G., Mc Carthy T.V., Marx A., et al. EphA3 is induced by CD28 and IGF-1 and regulates cell adhesion. Exp Cell Res 2004, 292:295-303.
24. Hafner C., Schmitz G., Meyer S., Bataille F., Hau P., Langmann T., et al. Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers. Clin Chem 2004, 50:490-499.
25. Kung B., Zhao H., Hicks S.L., Tang X.X., Ikegaki N. Biological significance of EPHA2 expression in neuroblastoma. Int J Oncol 2009, 35:845-850.
26. Li X., Wang L., Gu J.W., Li B., Liu W.P., Wang Y.G., et al. Up-regulation of EphA2 and down-regulation of ephrinA1 are associated with the aggressive phenotype and poor prognosis of malignant glioma. Tumour Biol 2010, 31:477-488.
27. Gopal U., Bohonowych J.E., Lema-Tome C., Liu A., Garrett-Mayer E., Wang B., et al. A novel extracellular Hsp90 mediated co-receptor function for LRP1 regulates EphA2 dependent glioblastoma cell invasion. PLoS One 2011, 6:e17649.
28. Walker-Daniels J., Coffman K., Azimi M., Rhim J.S., Bostwick D.G., Snyder P., et al. Overexpression of the EphA2 tyrosine kinase in prostate cancer. Prostate 1999, 41:275-280.
29. Miao H., Wei B.R., Peehl D.M., Li Q., Alexandrou T., Schelling J.R., et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat Cell Biol 2001, 3:527-530.
30. Robinson D., He F., Pretlow T., Kung H.J. A tyrosine kinase profile of prostate carcinoma. Proc Natl Acad Sci U S A 1996, 93:5958-5962.
31. McCarron J.K., Stringer B.W., Day B.W., Boyd A.W. Ephrin expression and function in cancer. Future Oncol 2010, 6:165-176.
32. Adams R.H., Wilkinson G.A., Weiss C., Diella F., Gale N.W., Deutsch U., et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 1999, 13:295-306.
33. Miao H., Li D.Q., Mukherjee A., Guo H., Petty A., Cutter J., et al. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell 2009, 16:9-20.
34. Wang B. Cancer cells exploit the eph-ephrin system to promote invasion and metastasis: tales of unwitting partners. Sci Signal 2011, 4:pe28.
35. Pasquale E.B. Eph-ephrin bidirectional signaling in physiology and disease. Cell 2008, 133:38-52.
36. Wykosky J., Debinski W. The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting. Mol Cancer Res 2008, 6:1795-1806.
37. Jackson D., Gooya J., Mao S., Kinneer K., Xu L., Camara M., et al. A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo. Cancer Res 2008, 68:9367-9374.
38. Lee J.W., Stone R.L., Lee S.J., Nam E.J., Roh J.W., Nick A.M., et al. EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma. Clin Cancer Res 2010, 16:2562-2570.
39. Tandon M., Vemula S.V., Mittal S.K. Emerging strategies for EphA2 receptor targeting for cancer therapeutics. Expert Opin Ther Targets 2011, 15:31-51.
40. Chen J., Zhuang G., Frieden L., Debinski W. Eph receptors and ephrins in cancer: common themes and controversies. Cancer Res 2008, 68:10031-10033.
41. Cohen P. Protein kinases - the major drug targets of the twenty-first century?. Nat Rev Drug Discov 2002, 1:309-315.
42. Pasquale E.B. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 2010, 10:165-180.
43. Himanen J.P., Henkemeyer M., Nikolov D.B. Crystal structure of the ligand-binding domain of the receptor tyrosine kinase EphB2. Nature 1998, 396:486-491.
44. Himanen J.P., Saha N., Nikolov D.B. Cell-cell signaling via Eph receptors and ephrins. Curr Opin Cell Biol 2007, 19:534-542.
45. Klein R. Bidirectional modulation of synaptic functions by Eph/ephrin signaling. Nat Neurosci 2009, 12:15-20.
46. Miao H., Wang B. Eph/ephrin signaling in epithelial development and homeostasis. Int J Biochem Cell Biol 2009, 41:762-770.
47. Lackmann M., Boyd A.W. Eph, a protein family coming of age: more confusion, insight, or complexity?. Sci Signal 2008, 1:re2.
48. Lemmon M.A., Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2010, 141:1117-1134.
49. Hubbard S.R., Miller W.T. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol 2007, 19:117-123.
50. Unified nomenclature for Eph family receptors and their ligands, the ephrins. Eph Nomenclature Committee. Cell 1997, 90:403-404.
51. Himanen J.P., Chumley M.J., Lackmann M., Li C., Barton W.A., Jeffrey P.D., et al. Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci 2004, 7:501-509.
52. Goldgur Y., Paavilainen S., Nikolov D., Himanen J.P. Structure of the ligand-binding domain of the EphB2 receptor at 2Å resolution. Acta Crystallogr Sect F Struct Biol Cryst Commun 2009, 65:71-74.
53. Himanen J.P., Nikolov D.B. Purification, crystallization and preliminary characterization of an Eph-B2/ephrin-B2 complex. Acta Crystallogr D Biol Crystallogr 2002, 58:533-535.
54. Himanen J.P., Rajashankar K.R., Lackmann M., Cowan C.A., Henkemeyer M., Nikolov D.B. Crystal structure of an Eph receptor-ephrin complex. Nature 2001, 414:933-938.
55. Koolpe M., Dail M., Pasquale E.B. An ephrin mimetic peptide that selectively targets the EphA2 receptor. J Biol Chem 2002, 277:46974-46979.
56. Murai K.K., Nguyen L.N., Koolpe M., McLennan R., Krull C.E., Pasquale E.B. Targeting the EphA4 receptor in the nervous system with biologically active peptides. Mol Cell Neurosci 2003, 24:1000-1011.
57. Koolpe M., Burgess R., Dail M., Pasquale E.B. EphB receptor-binding peptides identified by phage display enable design of an antagonist with ephrin-like affinity. J Biol Chem 2005, 280:17301-17311.
58. Chrencik J.E., Brooun A., Recht M.I., Kraus M.L., Koolpe M., Kolatkar A.R., et al. Structure and thermodynamic characterization of the EphB4/ephrin-B2 antagonist peptide complex reveals the determinants for receptor specificity. Structure 2006, 14:321-330.
59. Chrencik J.E., Brooun A., Recht M.I., Nicola G., Davis L.K., Abagyan R., et al. Three-dimensional structure of the EphB2 receptor in complex with an antagonistic peptide reveals a novel mode of inhibition. J Biol Chem 2007, 282:36505-36513.
60. Himanen J.P., Goldgur Y., Miao H., Myshkin E., Guo H., Buck M., et al. Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex. EMBO Rep 2009, 10:722-728.
61. Pabbisetty K.B., Yue X., Li C., Himanen J.P., Zhou R., Nikolov D.B., et al. Kinetic analysis of the binding of monomeric and dimeric ephrins to Eph receptors: correlation to function in a growth cone collapse assay. Protein Sci 2007, 16:355-361.
62. Qin H., Noberini R., Huan X., Shi J., Pasquale E.B., Song J. Structural characterization of the EphA4-ephrin-B2 complex reveals new features enabling Eph-ephrin binding promiscuity. J Biol Chem 2010, 285:644-654.
63. *ephrinB2 protein-protein interaction and receptor specificity. J Biol Chem 2006, 281:28185-28192.
64. Himanen J.P., Yermekbayeva L., Janes P.W., Walker J.R., Xu K., Atapattu L., et al. Architecture of Eph receptor clusters. Proc Natl Acad Sci U S A 2010, 107:10860-10865.
65. Seiradake E., Harlos K., Sutton G., Aricescu A.R., Jones E.Y. An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly. Nat Struct Mol Biol 2010, 17:398-402.
66. Qin H., Shi J., Noberini R., Pasquale E.B., Song J. Crystal structure and NMR binding reveal that two small molecule antagonists target the high affinity ephrin-binding channel of the EphA4 receptor. J Biol Chem 2008, 283:29473-29484.
67. Bowden T.A., Aricescu A.R., Nettleship J.E., Siebold C., Rahman-Huq N., Owens R.J., et al. Structural plasticity of Eph receptor A4 facilitates cross-class ephrin signaling. Structure 2009, 17:1386-1397.
68. Singla N., Goldgur Y., Xu K., Paavilainen S., Nikolov D.B., Himanen J.P. Crystal structure of the ligand-binding domain of the promiscuous EphA4 receptor reveals two distinct conformations. Biochem Biophys Res Commun 2010, 399:555-559.
69. Toth J., Cutforth T., Gelinas A.D., Bethoney K.A., Bard J., Harrison C.J. Crystal structure of an ephrin ectodomain. Dev Cell 2001, 1:83-92.
70. Nikolov D.B., Li C., Barton W.A., Himanen J.P. Crystal structure of the ephrin-B1 ectodomain: implications for receptor recognition and signaling. Biochemistry 2005, 44:10947-10953.
71. Nikolov D., Li C., Lackmann M., Jeffrey P., Himanen J. Crystal structure of the human ephrin-A5 ectodomain. Protein Sci 2007, 16:996-1000.
72. Xu K., Rajashankar K.R., Chan Y.P., Himanen J.P., Broder C.C., Nikolov D.B. Host cell recognition by the henipaviruses: crystal structures of the Nipah G attachment glycoprotein and its complex with ephrin-B3. Proc Natl Acad Sci U S A 2008, 105:9953-9958.
73. Ran X., Qin H., Liu J., Fan J.S., Shi J., Song J. NMR structure and dynamics of human ephrin-B2 ectodomain: the functionally critical C-D and G-H loops are highly dynamic in solution. Proteins 2008, 72:1019-1029.
74. Smith F.M., Vearing C., Lackmann M., Treutlein H., Himanen J., Chen K., et al. Dissecting the EphA3/ephrin-A5 interactions using a novel functional mutagenesis screen. J Biol Chem 2004, 279:9522-9531.
75. Stein E., Lane A.A., Cerretti D.P., Schoecklmann H.O., Schroff A.D., Van Etten R.L., et al. Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Genes Dev 1998, 12:667-678.
76. Davis S., Gale N.W., Aldrich T.H., Maisonpierre P.C., Lhotak V., Pawson T., et al. Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 1994, 266:816-819.
77. Noberini R., Koolpe M., Peddibhotla S., Dahl R., Su Y., Cosford N.D., et al. Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors. J Biol Chem 2008, 283:29461-29472.
78. Mitra S., Duggineni S., Koolpe M., Zhu X., Huang Z., Pasquale E.B. Structure-activity relationship analysis of peptides targeting the EphA2 receptor. Biochemistry 2010, 49:6687-6695.
79. Muir T.W. Studying protein structure and function using semisynthesis. Biopolymers 2008, 90:743-750.
80. Singla N., Himanen J.P., Muir T.W., Nikolov D.B. Toward the semisynthesis of multidomain transmembrane receptors: modification of Eph tyrosine kinases. Protein Sci 2008, 17:1740-1747.
81. Singla N., Erdjument-Bromage H., Himanen J.P., Muir T.W., Nikolov D.B. A semisynthetic Eph receptor tyrosine kinase provides insight into ligand-induced kinase activation. Chem Biol 2011, 18:361-371.
82. Oganesyan V., Damschroder M.M., Phipps S., Wilson S.D., Cook K.E., Wu H., et al. Crystallization and preliminary X-ray diffraction analysis of the complex of a human anti-ephrin type-A receptor 2 antibody fragment and its cognate antigen. Acta Crystallogr Sect F Struct Biol Cryst Commun 2010, 66:730-733.
83. Toomre D., Bewersdorf J. A new wave of cellular imaging. Annu Rev Cell Dev Biol 2010, 26:285-314.
84. Stewart M.P., Toyoda Y., Hyman A.A., Muller D.J. Force probing cell shape changes to molecular resolution. Trends Biochem Sci 2011.
85. Salaita K., Nair P.M., Petit R.S., Neve R.M., Das D., Gray J.W., et al. Restriction of receptor movement alters cellular response: physical force sensing by EphA2. Science 2010, 327:1380-1385.