Ephrin type-B receptor 4

Function

Receptor tyrosine kinase which binds promiscuously to 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. Together with its cognate ligand/functional ligand EFNB2, it is involved in the regulation of cell adhesion and migration, and plays a central role in heart morphogenesis, angiogenesis and blood vessel remodeling and permeability. EPHB4-mediated forward signaling controls cellular repulsion and segregation from EFNB2-expressing cells. Phosphorylates inactive tyrosine-protein kinase EPHB6 which promotes interaction of EPHB6 with SH2 domains, allowing it to recruit SH2 domain-containing signaling adapters.

Classification

Family (Pfam)

PF14575 EphA2_TM, PF25599 Ephrin_CRD, PF01404 Ephrin_lbd, PF07699 Ephrin_rec_like, PF00041 fn3, PF07714 PK_Tyr_Ser-Thr, PF00536 SAM_1

InterPro

EPH-B4_SAM, Eph_TM, EphB4_rcpt_lig-bd, Ephrin_rcpt_lig-bd_dom, Ephrin_rcpt_TKs, FN3_dom, FN3_sf, Galactose-bd-like_sf, Growth_fac_rcpt_cys_sf, Ig-like_fold, Kinase-like_dom_sf, Prot_kinase_dom, Protein_kinase_ATP_BS, SAM, SAM/pointed_sf, Ser-Thr/Tyr_kinase_cat_dom, Tyr-kin_ephrin_A/B_rcpt-like, Tyr_kinase_AS, Tyr_kinase_cat_dom, Tyr_kinase_ephrin_rcpt, Tyr_kinase_rcpt_V_CS

Functional cluster

Secreted Growth Factors & Cytokines

Experimental structures · PDB · 23

• 2BBA X-ray 1.65A
• 2E7H NMR
• 2HLE X-ray 2.05A
• 2QKQ X-ray 2.10A
• 2VWU X-ray 2.00A
• 2VWV X-ray 1.90A
• 2VWW X-ray 1.90A
• 2VWX X-ray 1.65A
• 2VWY X-ray 1.65A
• 2VWZ X-ray 1.65A
• 2VX0 X-ray 2.10A
• 2VX1 X-ray 1.65A
• … and 11 more

A predicted model is available from AlphaFold.

Gene Ontology · 13

• GO:0005829 cytosol
• GO:0070062 extracellular exosome
• GO:0005576 extracellular region
• GO:0005886 plasma membrane
• GO:0043235 receptor complex
• GO:0005524 ATP binding
• GO:0005003 ephrin receptor activity
• GO:0004714 transmembrane receptor protein tyrosine kinase activity
• GO:0001525 angiogenesis
• GO:0007155 cell adhesion
• GO:0002042 cell migration involved in sprouting angiogenesis
• GO:0048013 ephrin receptor signaling pathway
• GO:0003007 heart morphogenesis

Disease associations

• lymphatic malformation 7 MONDO:0015009
• capillary malformation-arteriovenous malformation 2 MONDO:0020785

Drugs targeting this protein · 4

• VANDETANIB inhibitor
• TESEVATINIB inhibitor
• JI-101 inhibitor
• TG100-801 inhibitor

Related proteins · sequence + function similarity

• Ephrin type-B receptor 4 0.99
• Ephrin type-A receptor 8 0.95
• Ephrin type-A receptor 8 0.94
• Ephrin type-B receptor 3 0.92
• Ephrin type-B receptor 6 0.91
• Ephrin type-B receptor 3 0.90
• Ephrin type-B receptor 6 0.90
• Ephrin type-B receptor 6 0.90
• Ephrin type-B receptor 6 0.90
• Ephrin type-A receptor 1 0.90
• Ephrin type-A receptor 2 0.89
• Ephrin type-A receptor 10 0.89

Co-cited proteins · studied together in the literature

• Ephrin-B2 2 shared papers
• Ephrin type-B receptor 4a 1 shared papers
• Mesoderm induction early response protein 2 1 shared papers
• Ephrin type-B receptor 6 1 shared papers
• Ephrin type-A receptor 10 1 shared papers
• Ras GTPase-activating protein 1 1 shared papers
• Ephrin type-B receptor 4 2 shared papers
• Ephrin type-A receptor 1 2 shared papers
• Ephrin type-A receptor 7 1 shared papers
• Ephrin type-B receptor 3 1 shared papers
• Ephrin type-B receptor 1 2 shared papers
• Ephrin type-A receptor 5 1 shared papers

Literature · 23 cited papers

• The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs. Biochem. J. · 2021
• Mutations in chromatin modifier and ephrin signaling genes in vein of Galen malformation. Neuron · 2019
• Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation. Brain · 2018
• EPHB4 mutation implicated in capillary malformation-arteriovenous malformation syndrome: A case report. Pediatr. Dermatol. · 2017
• Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation · 2017
• EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis. J. Clin. Invest. · 2016
• An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
• Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Anal. Chem. · 2009
• Large-scale proteomics analysis of the human kinome. Mol. Cell. Proteomics · 2009
• Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol. Cell · 2008
• … and 11 more in the literature graph