DB code: M00124

RLCP classification	3.103.130000.1162 : Transfer
CATH domain	2.60.120.260 : Jelly Rolls
	-.-.-.- :
	2.60.40.30 : Immunoglobulin-like
	2.60.40.30 : Immunoglobulin-like
	3.30.200.20 : Phosphorylase Kinase; domain 1
	1.10.510.10 : Transferase(Phosphotransferase); domain 1	Catalytic domain
	1.10.150.50 : DNA polymerase; domain 1
E.C.	2.7.10.1
CSA
M-CSA
MACiE

CATH domain	Related DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1	M00125 M00131 T00224 M00127 M00129 M00130 M00132 M00136 M00196 M00197 M00198 M00304 M00323 M00325 M00326 M00327 M00328 M00329 M00330 M00331 M00332 M00333 M00335 M00339 M00344
2.60.120.260 : Jelly Rolls	T00005 T00065 T00066
2.60.40.30 : Immunoglobulin-like	M00134 M00129 M00136 M00149 M00192
3.30.200.20 : Phosphorylase Kinase; domain 1	M00125 M00131 T00224 M00127 M00129 M00130 M00132 M00136 M00196 M00197 M00198 M00304 M00323 M00325 M00326 M00327 M00328 M00329 M00330 M00331 M00332 M00333 M00335 M00339 M00344 D00298

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	Pfam	RefSeq
P54763	Ephrin type-B receptor 2	EC 2.7.10.1 Tyrosine-protein kinase receptor EPH-3 Neural kinase Nuk receptor tyrosine kinase SEK-3	PF01404 (Ephrin_lbd) PF00041 (fn3) PF07699 (GCC2_GCC3) PF07714 (Pkinase_Tyr) PF00536 (SAM_1) [Graphical View]
P28693	Ephrin type-B receptor 2	EC 2.7.10.1 Tyrosine-protein kinase receptor CEK5	PF01404 (Ephrin_lbd) PF00041 (fn3) PF07699 (GCC2_GCC3) PF07714 (Pkinase_Tyr) PF00536 (SAM_1) [Graphical View]	NP_996834.1 (Protein) NM_206951.3 (DNA/RNA sequence)

KEGG enzyme name

receptor protein-tyrosine kinase AATK AATYK AATYK2 AATYK3 ACH ALK anaplastic lymphoma kinase ARK ATP:protein-tyrosine O-phosphotransferase (ambiguous) AXL Bek Bfgfr BRT Bsk C-FMS CAK CCK4 CD115 CD135 CDw135 Cek1 Cek10 Cek11 Cek2 Cek3 Cek5 Cek6 Cek7 CFD1 CKIT CSF1R DAlk DDR1 DDR2 Dek DKFZp434C1418 Drosophila Eph kinase DRT DTK Ebk ECK EDDR1 Eek EGFR Ehk2 Ehk3 Elk EPH EPHA1 EPHA2 EPHA6 EPHA7 EPHA8 EPHB1 EPHB2 EPHB3 EPHB4 EphB5 ephrin-B3 receptor tyrosine kinase EPHT EPHT2 EPHT3 EPHX ERBB ERBB1 ERBB2 ERBB3 ERBB4 ERK Eyk FGFR1 FGFR2 FGFR3 FGFR4 FLG FLK1 FLK2 FLT1 FLT2 FLT3 FLT4 FMS Fv2 HBGFR HEK11 HEK2 HEK3 HEK5 HEK6 HEP HER2 HER3 HER4 HGFR HSCR1 HTK IGF1R INSR INSRR insulin receptor protein-tyrosine kinase IR IRR JTK12 JTK13 JTK14 JWS K-SAM KDR KGFR KIA0641 KIAA1079 KIAA1459 Kil Kin15 Kin16 KIT KLG LTK MCF3 Mdk1 Mdk2 Mdk5 MEhk1 MEN2A/B Mep MER MERTK MET Mlk1 Mlk2 Mrk MST1R MTC1 MUSK Myk1 N-SAM NEP NET Neu neurite outgrowth regulating kinase NGL NOK nork novel oncogene with kinase-domain Nsk2 NTRK1 NTRK2 NTRK3 NTRK4 NTRKR1 NTRKR2 NTRKR3 Nuk NYK PCL PDGFR PDGFRA PDGFRB PHB6 protein-tyrosine kinase (ambiguous) protein tyrosine kinase (ambiguous) PTK PTK3 PTK7 receptor protein tyrosine kinase RET RON ROR1 ROR2 ROS1 RSE RTK RYK SEA Sek2 Sek3 Sek4 Sfr SKY STK STK1 TEK TIE TIE1 TIE2 TIF TKT TRK TRKA TRKB TRKC TRKE TYK1 TYRO10 Tyro11 TYRO3 Tyro5 Tyro6 TYRO7 UFO VEGFR1 VEGFR2 VEGFR3 Vik YK1 Yrk

UniprotKB: Accession Number	Entry name	Activity	Subunit	Subcellular location	Cofactor
P54763	EPHB2_MOUSE	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.	Interacts with PRKCABP. The ligand-activated form interacts with multiple proteins, including GTPase-activating protein (RASGAP) through its SH2 domain. Binds RASGAP through the juxtamembrane tyrosines residues (By similarity). Interacts with PRKCABP and GRIP1.	Membrane, Single-pass type I membrane protein.
P28693	EPHB2_CHICK	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.		Membrane, Single-pass type I membrane protein.

KEGG Pathways
Map code	Pathways	E.C.

Compound table
						Cofactors	Substrates		Products		Intermediates
KEGG-id						C00305	C00002	C00585	C00008	C01167
E.C.
Compound						Magnesium	ATP	[Protein]-L-tyrosine	ADP	[Protein]-L-tyrosine phosphate
Type						divalent metal (Ca2+, Mg2+)	amine group,nucleotide	aromatic ring (only carbon atom),peptide/protein	amine group,nucleotide	aromatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion
ChEBI						18420 18420	15422 15422		16761 16761
PubChem						888 888	5957 5957		6022 6022
1nukA						Unbound	Unbound	Unbound	Unbound	Unbound
1kgyA						Unbound	Unbound	Unbound	Unbound	Unbound
1kgyB						Unbound	Unbound	Unbound	Unbound	Unbound
1kgyC						Unbound	Unbound	Unbound	Unbound	Unbound
1kgyD						Unbound	Unbound	Unbound	Unbound	Unbound
1jpaA01						Unbound	Unbound	Unbound	Analogue:ANP	Unbound
1jpaB01						Unbound	Unbound	Unbound	Analogue:ANP	Unbound
1jpaA02						Unbound	Unbound	Unbound	Unbound	Unbound
1jpaB02						Unbound	Unbound	Unbound	Unbound	Unbound
1sggA						Unbound	Unbound	Unbound	Unbound	Unbound

Reference for Active-site residues
resource	references	E.C.
Swiss-prot & Similarity with M00129

Active-site residues
PDB						Catalytic residues	Cofactor-binding residues	Modified residues	Main-chain involved in catalysis	Comment
1nukA
1kgyA
1kgyB
1kgyC
1kgyD
1jpaA01										mutant Y604F, Y610F
1jpaB01										mutant Y604F, Y610F
1jpaA02						ASP 754;ARG 758	ASN 759;ASP 772(Magnesium binding)
1jpaB02						ASP 754;ARG 758	ASN 759;ASP 772(Magnesium binding)
1sggA								TYR 25 (Phospholylated)

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[9]
[10]

References
[1]
Resource
Comments
Medline ID
PubMed ID	9233798
Journal	EMBO J
Year	1997
Volume	16
Pages	3877-88
Authors	Holland SJ, Gale NW, Gish GD, Roth RA, Songyang Z, Cantley LC, Henkemeyer M, Yancopoulos GD, Pawson T
Title	Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells.
Related PDB
Related UniProtKB
[2]
Resource
Comments	X-ray crystallography
Medline ID
PubMed ID	9853759
Journal	Nature
Year	1998
Volume	396
Pages	486-91
Authors	Himanen JP, Henkemeyer M, Nikolov DB
Title	Crystal structure of the ligand-binding domain of the receptor tyrosine kinase EphB2.
Related PDB	1nuk
Related UniProtKB
[3]
Resource
Comments	INTERACTION WITH PRKCABP
Medline ID	99098206
PubMed ID	9883737
Journal	Neuron
Year	1998
Volume	21
Pages	1453-63
Authors	Torres R, Firestein BL, Dong H, Staudinger J, Olson EN, Huganir RL, Bredt DS, Gale NW, Yancopoulos GD
Title	PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands.
Related PDB
Related UniProtKB	P54763
[4]
Resource
Comments
Medline ID
PubMed ID	9632142
Journal	Oncogene
Year	1998
Volume	16
Pages	2657-70
Authors	Zisch AH, Kalo MS, Chong LD, Pasquale EB
Title	Complex formation between EphB2 and Src requires phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID	10523848
Journal	Oncogene
Year	1999
Volume	18
Pages	5680-90
Authors	Yoshii S, Tanaka M, Otsuki Y, Wang DY, Guo RJ, Zhu Y, Takeda R, Hanai H, Kaneko E, Sugimura H
Title	alphaPIX nucleotide exchange factor is activated by interaction with phosphatidylinositol 3-kinase.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID	10555534
Journal	Cell Tissue Res
Year	1999
Volume	298
Pages	1-9
Authors	Kalo MS, Pasquale EB
Title	Signal transfer by Eph receptors.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID	10356296
Journal	Mol Cell Neurosci
Year	1999
Volume	13
Pages	337-47
Authors	Scully AL, McKeown M, Thomas JB
Title	Isolation and characterization of Dek, a Drosophila eph receptor protein tyrosine kinase.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID	10449409
Journal	EMBO J
Year	1999
Volume	18
Pages	4438-45
Authors	Chi SW, Ayed A, Arrowsmith CH
Title	Solution structure of a conserved C-terminal domain of p73 with structural homology to the SAM domain.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID	9886291
Journal	Nat Struct Biol
Year	1999
Volume	6
Pages	44-9
Authors	Stapleton D, Balan I, Pawson T, Sicheri F
Title	The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization.
Related PDB
Related UniProtKB
[10]
Resource
Comments	NMR Structures
Medline ID
PubMed ID	10548040
Journal	Protein Sci
Year	1999
Volume	8
Pages	1954-61
Authors	Smalla M, Schmieder P, Kelly M, Ter Laak A, Krause G, Ball L, Wahl M, Bork P, Oschkinat H
Title	Solution structure of the receptor tyrosine kinase EphB2 SAM domain and identification of two distinct homotypic interaction sites.
Related PDB	1sgg
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID	9933164
Journal	Science
Year	1999
Volume	283
Pages	833-6
Authors	Thanos CD, Goodwill KE, Bowie JU
Title	Oligomeric structure of the human EphB2 receptor SAM domain.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID	10848605
Journal	Mol Cell Biol
Year	2000
Volume	20
Pages	4791-805
Authors	Binns KL, Taylor PP, Sicheri F, Pawson T, Holland SJ
Title	Phosphorylation of tyrosine residues in the kinase domain and juxtamembrane region regulates the biological and catalytic activities of Eph receptors.
Related PDB
Related UniProtKB
[13]
Resource
Comments	FUNCTION
Medline ID	20171264
PubMed ID	10704386
Journal	Development
Year	2000
Volume	127
Pages	1397-410
Authors	Imondi R, Wideman C, Kaprielian Z
Title	Complementary expression of transmembrane ephrins and their receptors in the mouse spinal cord: a possible role in constraining the orientation of longitudinally projecting axons.
Related PDB
Related UniProtKB	P54763
[14]
Resource
Comments
Medline ID
PubMed ID	11572780
Journal	Cell
Year	2001
Volume	106
Pages	745-57
Authors	Wybenga-Groot LE, Baskin B, Ong SH, Tong J, Pawson T, Sicheri F
Title	Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region.
Related PDB	1jpa
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID	11780069
Journal	Nature
Year	2001
Volume	414
Pages	933-8
Authors	Himanen JP, Rajashankar KR, Lackmann M, Cowan CA, Henkemeyer M, Nikolov DB
Title	Crystal structure of an Eph receptor-ephrin complex.
Related PDB	1kgy
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID	11718293
Journal	Eur Biophys J
Year	2001
Volume	30
Pages	411-5
Authors	Behlke J, Labudde D, Ristau O
Title	Self-association studies on the EphB2 receptor SAM domain using analytical ultracentrifugation.
Related PDB
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID	12054873
Journal	J Mol Biol
Year	2002
Volume	319
Pages	823-37
Authors	Baldisseri DM, Margolis JW, Weber DJ, Koo JH, Margolis FL
Title	Olfactory marker protein (OMP) exhibits a beta-clam fold in solution: implications for target peptide interaction and olfactory signal transduction.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID	12054872
Journal	J Mol Biol
Year	2002
Volume	319
Pages	807-21
Authors	Smith PC, Firestein S, Hunt JF
Title	The crystal structure of the olfactory marker protein at 2.3 A resolution.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID	12141423
Journal	Int J Dev Biol
Year	2002
Volume	46
Pages	375-84
Authors	Coulthard MG, Duffy S, Down M, Evans B, Power M, Smith F, Stylianou C, Kleikamp S, Oates A, Lackmann M, Burns GF, Boyd AW
Title	The role of the Eph-ephrin signalling system in the regulation of developmental patterning.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID	12528767
Journal	Eur J Cancer
Year	2002
Volume	38 Suppl 5
Pages	S3-10
Authors	Pawson T
Title	Regulation and targets of receptor tyrosine kinases.
Related PDB
Related UniProtKB
[21]
Resource
Comments
Medline ID
PubMed ID	12100883
Journal	Curr Opin Genet Dev
Year	2002
Volume	12
Pages	397-402
Authors	Drescher U
Title	Eph family functions from an evolutionary perspective.
Related PDB
Related UniProtKB

Comments

The E.C. was transferred from 2.7.1.112 to 2.7.10.1. The Eph receptor tyrosine kinase family is regulated by autophosphorylation within the juxtamembrane region and the kinase activation segment. This receptor enzyme has N-terminal extracellular region, which is composed of ligand-binding domain, Cys-rich domain, and two fibronectine type-III domain, transmembrane region, and cytoplasmic region, which is composed of juxtamembrane region, protein kinase domain, and SAM domain. PDB structures, 1nuk & 1kgy, correspond to the first domain of this enzyme, ligand-binding domain, the other structure, 1jpa, comprises the fifth domain, juxtamembrane region, and the sixth domain, protein kinase domain. PDB structure, 1sgg, corresponds to the last domain, SAM. However, tertiary structures of the rest of domains, the second domain, Cys-rich domain, the third and fourth domains, two fibronectin type-III domains, have not been determined yet. The last domain is sterile alpha motif (SAM) domain, which was found in various signaling proteins such as tyrosine and serine/threonine protein kinases, regulators of lipid metabolism, and GTPases, according to the literature [9]. The SAM domain is involved in protein-protein interaction, rather than catalysis, through the ability to oligomerize with other SAM domains [9]. This SAM domain has a conserved tyrosine (Tyr25, PDB;1sgg), which was reported to be essential for the interaction with SH2 domains after its phosphorylation (see paper [10]). Although the tertiary structure of the catalytic domain has been determined, its catalytic mechanism is still unclear. However, since the structure is homologous to other kinase domains with complete conservation of active site residues, the mechanism can be similar to those ones (see M00129).

Created	Updated
2003-07-22	2009-02-26