D
IPR030602

Ephrin type-A receptor 4, SAM domain

InterPro entry
Short nameEphA4_SAM
Overlapping
homologous
superfamilies
 
domain relationships

Description

This entry represents the SAM domain of EPH-A4. It is a C-terminal potential protein-protein interaction domain
[17]
.

Ephrin receptors (Ephs) are a group of receptor tyrosine kinases that are activated in response to binding ephrin ligands residing on adjacent cells, leading to contact-dependent bidirectional signalling into neighbouring cells
[6]
.

Ephrin type-A receptor 4 (EphA4) is highly promiscuou; 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
[11]
. It is involved in development
[7, 8]
, supporting spine maturation
[1, 10, 9]
, axon guidance
[5, 2]
and assembly of neuronal locomotor circuits
[2, 3]
. EphA4 is the most abundant ephrin receptor in the nervous system. Mice lacking the EphA4 exhibit pronounced axonal regeneration and functional recovery following spinal cord injury
[4, 12, 13]
. In humans EphA4 has been proposed to be a key actor in neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS)
[15]
. Inhibition of the EphA4-ephrin interaction has been considered as a useful strategy for promoting axon regeneration in the nervous system and a pharmacological tool to treat neurodegenerative disease patients
[14, 16]
.

References

1.EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Dottori M, Hartley L, Galea M, Paxinos G, Polizzotto M, Kilpatrick T, Bartlett PF, Murphy M, Kontgen F, Boyd AW. Proc. Natl. Acad. Sci. U.S.A. 95, 13248-53, (1998). View articlePMID: 9789074

2.Role of EphA4 and EphrinB3 in local neuronal circuits that control walking. Kullander K, Butt SJ, Lebret JM, Lundfald L, Restrepo CE, Rydstrom A, Klein R, Kiehn O. Science 299, 1889-92, (2003). View articlePMID: 12649481

3.alpha2-Chimaerin is an essential EphA4 effector in the assembly of neuronal locomotor circuits. Beg AA, Sommer JE, Martin JH, Scheiffele P. Neuron 55, 768-78, (2007). View articlePMID: 17785183

4.Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. Goldshmit Y, Galea MP, Wise G, Bartlett PF, Turnley AM. J. Neurosci. 24, 10064-73, (2004). View articlePMID: 15537875

5.EphA4 Receptor Shedding Regulates Spinal Motor Axon Guidance. Gatto G, Morales D, Kania A, Klein R. Curr. Biol. 24, 2355-65, (2014). View articlePMID: 25264256

6.Mechanisms and functions of Eph and ephrin signalling. Kullander K, Klein R. Nat. Rev. Mol. Cell Biol. 3, 475-86, (2002). View articlePMID: 12094214

7.EphA4-dependent Brachyury expression is required for dorsal mesoderm involution in the Xenopus gastrula. Evren S, Wen JW, Luu O, Damm EW, Nagel M, Winklbauer R. Development 141, 3649-61, (2014). View articlePMID: 25209247

8.Ephrin-B2/EphA4 forward signaling is required for regulation of radial migration of cortical neurons in the mouse. Hu Y, Li S, Jiang H, Li MT, Zhou JW. Neurosci Bull 30, 425-32, (2014). View articlePMID: 24477991

9.EphrinB3/EphA4-mediated guidance of ascending and descending spinal tracts. Paixao S, Balijepalli A, Serradj N, Niu J, Luo W, Martin JH, Klein R. Neuron 80, 1407-20, (2013). View articlePMID: 24360544

10.EphA4 expression promotes network activity and spine maturation in cortical neuronal cultures. Clifford MA, Kanwal JK, Dzakpasu R, Donoghue MJ. Neural Dev 6, 21, (2011). View articlePMID: 21542907

11.Crystal structure of the ligand-binding domain of the promiscuous EphA4 receptor reveals two distinct conformations. Singla N, Goldgur Y, Xu K, Paavilainen S, Nikolov DB, Himanen JP. Biochem. Biophys. Res. Commun. 399, 555-9, (2010). View articlePMID: 20678482

12.EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice. Goldshmit Y, Spanevello MD, Tajouri S, Li L, Rogers F, Pearse M, Galea M, Bartlett PF, Boyd AW, Turnley AM. PLoS ONE 6, e24636, (2011). View articlePMID: 21931787

13.Expression and activation of EphA4 in the human brain after traumatic injury. Frugier T, Conquest A, McLean C, Currie P, Moses D, Goldshmit Y. J. Neuropathol. Exp. Neurol. 71, 242-50, (2012). View articlePMID: 22318127

14.Modifying expression of EphA4 and its downstream targets improves functional recovery after stroke. Lemmens R, Jaspers T, Robberecht W, Thijs VN. Hum. Mol. Genet. 22, 2214-20, (2013). View articlePMID: 23418304

15.EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Van Hoecke A, Schoonaert L, Lemmens R, Timmers M, Staats KA, Laird AS, Peeters E, Philips T, Goris A, Dubois B, Andersen PM, Al-Chalabi A, Thijs V, Turnley AM, van Vught PW, Veldink JH, Hardiman O, Van Den Bosch L, Gonzalez-Perez P, Van Damme P, Brown RH Jr, van den Berg LH, Robberecht W. Nat. Med. 18, 1418-22, (2012). View articlePMID: 22922411

16.Are We Using the Right Pharmacological Tools to Target EphA4? Tognolini M, Incerti M, Lodola A. ACS Chem Neurosci 5, 1146-7, (2014). View articlePMID: 25405504

17.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. 6, 44-9, (1999). View articlePMID: 9886291

Further reading

18. EphA4 receptor is a novel negative regulator of osteoclast activity. Stiffel V, Amoui M, Sheng MH, Mohan S, Lau KH. J. Bone Miner. Res. 29, 804-19, (2014). View articlePMID: 23983218

19. Discovery and characterization of a novel cyclic peptide that effectively inhibits ephrin binding to the EphA4 receptor and displays anti-angiogenesis activity. Han X, Xu Y, Yang Y, Xi J, Tian W, Duggineni S, Huang Z, An J. PLoS ONE 8, e80183, (2013). View articlePMID: 24265799

20. [Eph family receptors as therapeutic targets]. Zozulya SA, Udovichenko IP. Bioorg. Khim. 38, 267-79, (2012). View articlePMID: 22997698

21. Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers. Oki M, Yamamoto H, Taniguchi H, Adachi Y, Imai K, Shinomura Y. World J. Gastroenterol. 14, 5650-6, (2008). PMID: 18837080

Cross References

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