| Structural highlights
2hen is a 4 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 2hel, 1jpa |
| Gene: | Ephb2, Epth3, Nuk, Sek3 (LK3 transgenic mice) |
| Activity: | Receptor protein-tyrosine kinase, with EC number 2.7.10.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum |
Function
[EPHB2_MOUSE] Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Functions in axon guidance during development. Involved in the guidance of commissural axons, that form a major interhemispheric connection between the 2 temporal lobes of the cerebral cortex. Also involved in guidance of contralateral inner ear efferent growth cones at the midline and of retinal ganglion cell axons to the optic disk. Beside axon guidance, also regulates dendritic spines development and maturation and stimulates the formation of excitatory synapses. Upon activation by EFNB1, abolishes the ARHGEF15-mediated negative regulation on excitatory synapse formation. Controls other aspects of development including angiogenesis, palate development and in inner ear development through regulation of endolymph production. Forward and reverse signaling through the EFNB2/EPHB2 complex regulate movement and adhesion of cells that tubularize the urethra and septate the cloaca. May function as a tumor suppressor.[1] [2] [3] [4] [5] [6] [7]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Eph receptor tyrosine kinases (RTKs) mediate numerous developmental processes. Their activity is regulated by auto-phosphorylation on two tyrosines within the juxtamembrane segment (JMS) immediately N-terminal to the kinase domain (KD). Here, we probe the molecular details of Eph kinase activation through mutational analysis, X-ray crystallography and NMR spectroscopy on auto-inhibited and active EphB2 and EphA4 fragments. We show that a Tyr750Ala gain-of-function mutation in the KD and JMS phosphorylation independently induce disorder of the JMS and its dissociation from the KD. Our X-ray analyses demonstrate that this occurs without major conformational changes to the KD and with only partial ordering of the KD activation segment. However, conformational exchange for helix alphaC in the N-terminal KD lobe and for the activation segment, coupled with increased inter-lobe dynamics, is observed upon kinase activation in our NMR analyses. Overall, our results suggest that a change in inter-lobe dynamics and the sampling of catalytically competent conformations for helix alphaC and the activation segment rather than a transition to a static active conformation underlies Eph RTK activation.
A change in conformational dynamics underlies the activation of Eph receptor tyrosine kinases.,Wiesner S, Wybenga-Groot LE, Warner N, Lin H, Pawson T, Forman-Kay JD, Sicheri F EMBO J. 2006 Oct 4;25(19):4686-96. Epub 2006 Sep 14. PMID:16977320[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Henkemeyer M, Orioli D, Henderson JT, Saxton TM, Roder J, Pawson T, Klein R. Nuk controls pathfinding of commissural axons in the mammalian central nervous system. Cell. 1996 Jul 12;86(1):35-46. PMID:8689685
- ↑ Orioli D, Henkemeyer M, Lemke G, Klein R, Pawson T. Sek4 and Nuk receptors cooperate in guidance of commissural axons and in palate formation. EMBO J. 1996 Nov 15;15(22):6035-49. PMID:8947026
- ↑ Adams RH, Wilkinson GA, Weiss C, Diella F, Gale NW, Deutsch U, Risau W, Klein R. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 1999 Feb 1;13(3):295-306. PMID:9990854
- ↑ Cowan CA, Yokoyama N, Bianchi LM, Henkemeyer M, Fritzsch B. EphB2 guides axons at the midline and is necessary for normal vestibular function. Neuron. 2000 May;26(2):417-30. PMID:10839360
- ↑ Henkemeyer M, Itkis OS, Ngo M, Hickmott PW, Ethell IM. Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus. J Cell Biol. 2003 Dec 22;163(6):1313-26. PMID:14691139 doi:http://dx.doi.org/10.1083/jcb.200306033
- ↑ Dravis C, Yokoyama N, Chumley MJ, Cowan CA, Silvany RE, Shay J, Baker LA, Henkemeyer M. Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development. Dev Biol. 2004 Jul 15;271(2):272-90. PMID:15223334 doi:http://dx.doi.org/10.1016/j.ydbio.2004.03.027
- ↑ Margolis SS, Salogiannis J, Lipton DM, Mandel-Brehm C, Wills ZP, Mardinly AR, Hu L, Greer PL, Bikoff JB, Ho HY, Soskis MJ, Sahin M, Greenberg ME. EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell. 2010 Oct 29;143(3):442-55. doi: 10.1016/j.cell.2010.09.038. PMID:21029865 doi:http://dx.doi.org/10.1016/j.cell.2010.09.038
- ↑ Wiesner S, Wybenga-Groot LE, Warner N, Lin H, Pawson T, Forman-Kay JD, Sicheri F. A change in conformational dynamics underlies the activation of Eph receptor tyrosine kinases. EMBO J. 2006 Oct 4;25(19):4686-96. Epub 2006 Sep 14. PMID:16977320
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