| Structural highlights
Function
[EPHA4_MOUSE] Receptor tyrosine kinase which binds membrane-bound ephrin 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. Highly promiscuous, it has the unique property among Eph receptors to bind and to be physiologically activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1 and EFNB3. Upon activation by ephrin ligands, modulates cell morphology and integrin-dependent cell adhesion through regulation of the Rac, Rap and Rho GTPases activity. Plays an important role in the development of the nervous system controlling different steps of axonal guidance including the establishment of the corticospinal projections. May also control the segregation of motor and sensory axons during neuromuscular circuit development. Beside its role in axonal guidance plays a role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at 'Tyr-15' which in turn phosphorylates NGEF regulating RHOA and dendritic spine morphogenesis. In the nervous system, plays also a role in repair after injury preventing axonal regeneration and in angiogenesis playing a role in central nervous system vascular formation. Additionally, its promiscuity makes it available to participate in a variety of cell-cell signaling regulating for instance the development of the thymic epithelium.[1] [2] [3] [4] [5] [6] [7] [8] [9]
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
The sterile alpha motif (SAM) domain is a novel protein module of approximately 70 amino acids that is found in a variety of signaling molecules including tyrosine and serine/threonine protein kinases, cytoplasmic scaffolding and adaptor proteins, regulators of lipid metabolism, and GTPases as well as members of the ETS family of transcription factors. The SAM domain can potentially function as a protein interaction module through the ability to homo- and hetero-oligomerize with other SAM domains. This functional property elicits the oncogenic activation of chimeric proteins arising from translocation of the SAM domain of TEL to coding regions of the betaPDGF receptor, Abl, JAK2 protein kinase and the AML1 transcription factor. Here we describe the 2.0 A X-ray crystal structure of a SAM domain homodimer from the intracellular region of the EphA4 receptor tyrosine kinase. The structure reveals a mode of dimerization that we predict is shared amongst the SAM domains of the Eph receptor tyrosine kinases and possibly other SAM domain containing proteins. These data indicate a mechanism through which an independently folding protein module can form homophilic complexes that regulate signaling events at the membrane and in the nucleus.
The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization.,Stapleton D, Balan I, Pawson T, Sicheri F Nat Struct Biol. 1999 Jan;6(1):44-9. PMID:9886291[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dottori M, Hartley L, Galea M, Paxinos G, Polizzotto M, Kilpatrick T, Bartlett PF, Murphy M, Kontgen F, Boyd AW. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13248-53. PMID:9789074
- ↑ Goldshmit Y, Galea MP, Wise G, Bartlett PF, Turnley AM. Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. J Neurosci. 2004 Nov 10;24(45):10064-73. PMID:15537875 doi:http://dx.doi.org/10.1523/JNEUROSCI.2981-04.2004
- ↑ Goldshmit Y, Galea MP, Bartlett PF, Turnley AM. EphA4 regulates central nervous system vascular formation. J Comp Neurol. 2006 Aug 20;497(6):864-75. PMID:16802330 doi:http://dx.doi.org/10.1002/cne.21029
- ↑ Munoz JJ, Alfaro D, Garcia-Ceca J, Alonso-C LM, Jimenez E, Zapata A. Thymic alterations in EphA4-deficient mice. J Immunol. 2006 Jul 15;177(2):804-13. PMID:16818734
- ↑ Iwasato T, Katoh H, Nishimaru H, Ishikawa Y, Inoue H, Saito YM, Ando R, Iwama M, Takahashi R, Negishi M, Itohara S. Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling. Cell. 2007 Aug 24;130(4):742-53. PMID:17719550 doi:http://dx.doi.org/10.1016/j.cell.2007.07.022
- ↑ Richter M, Murai KK, Bourgin C, Pak DT, Pasquale EB. The EphA4 receptor regulates neuronal morphology through SPAR-mediated inactivation of Rap GTPases. J Neurosci. 2007 Dec 19;27(51):14205-15. PMID:18094260 doi:http://dx.doi.org/10.1523/JNEUROSCI.2746-07.2007
- ↑ Fu WY, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH, Fu AK, Greenberg ME, Ip NY. Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci. 2007 Jan;10(1):67-76. Epub 2006 Dec 3. PMID:17143272 doi:10.1038/nn1811
- ↑ Beg AA, Sommer JE, Martin JH, Scheiffele P. alpha2-Chimaerin is an essential EphA4 effector in the assembly of neuronal locomotor circuits. Neuron. 2007 Sep 6;55(5):768-78. PMID:17785183 doi:http://dx.doi.org/10.1016/j.neuron.2007.07.036
- ↑ Gallarda BW, Bonanomi D, Muller D, Brown A, Alaynick WA, Andrews SE, Lemke G, Pfaff SL, Marquardt T. Segregation of axial motor and sensory pathways via heterotypic trans-axonal signaling. Science. 2008 Apr 11;320(5873):233-6. doi: 10.1126/science.1153758. PMID:18403711 doi:http://dx.doi.org/10.1126/science.1153758
- ↑ Stapleton D, Balan I, Pawson T, Sicheri F. The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization. Nat Struct Biol. 1999 Jan;6(1):44-9. PMID:9886291 doi:10.1038/4917
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