DB code: M00326

RLCP classification 3.103.130000.1162 : Transfer
CATH domain 2.60.-.- :
2.60.40.60 : Immunoglobulin-like
2.60.-.- :
2.60.-.- :
-.-.-.- :
-.-.-.- :
-.-.-.- :
3.30.200.20 : Phosphorylase Kinase; domain 1
1.10.510.10 : Transferase(Phosphotransferase); domain 1 Catalytic domain
-.-.-.- :
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 M00124 M00131 T00224 M00127 M00129 M00130 M00132 M00136 M00196 M00197 M00198 M00304 M00323 M00325 M00327 M00328 M00329 M00330 M00331 M00332 M00333 M00335 M00339 M00344
3.30.200.20 : Phosphorylase Kinase; domain 1 M00125 M00124 M00131 T00224 M00127 M00129 M00130 M00132 M00136 M00196 M00197 M00198 M00304 M00323 M00325 M00327 M00328 M00329 M00330 M00331 M00332 M00333 M00335 M00339 M00344 D00298

Uniprot Enzyme Name
UniprotKB Protein name Synonyms Contains RefSeq Pfam
P07949 Proto-oncogene tyrosine-protein kinase receptor Ret
EC 2.7.10.1
Cadherin family member 12
Proto-oncogene c-Ret
Soluble RET kinase fragment
Extracellular cell-membrane anchored RET cadherin 120 kDa fragment
NP_065681.1 (Protein)
NM_020630.4 (DNA/RNA sequence)
NP_066124.1 (Protein)
NM_020975.4 (DNA/RNA sequence)
PF00028 (Cadherin)
PF07714 (Pkinase_Tyr)
[Graphical View]

KEGG enzyme name
Receptor protein-tyrosine kinase
ATP:protein-tyrosine O-phosphotransferase (ambiguous)
Protein-tyrosine kinase (ambiguous)
Protein tyrosine kinase (ambiguous)
Receptor protein tyrosine kinase
RET

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P07949 RET_HUMAN ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5. The phosphorylated form interacts with PLCG1 and GRB7 (By similarity). Interacts (not phosphorylated) with CC PTK2/FAK1 (via FERM domain). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas. Interacts with AIP in the pituitary gland, this interaction prevents the formation of the AIP-survivin complex. Binds to ARTN. Cell membrane, Single-pass type I membrane protein. Endosome 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 Mg 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
2x2uA01 Unbound Unbound Unbound Unbound Unbound
2x2uA02 Unbound Unbound Unbound Unbound Unbound
2ivsA01 Unbound Unbound Unbound Analogue:ACK Unbound
2ivsB01 Unbound Unbound Unbound Analogue:ACK Unbound
2ivtA01 Unbound Unbound Unbound Analogue:AMP Unbound
2ivuA01 Unbound Unbound Unbound Unbound Unbound
2ivvA01 Unbound Unbound Unbound Unbound Unbound
2x2kA01 Unbound Unbound Unbound Unbound Unbound
2x2lA01 Unbound Unbound Unbound Unbound Unbound
2x2mA01 Unbound Unbound Unbound Unbound Unbound
2x2mB01 Unbound Unbound Unbound Unbound Unbound
2ivsA02 Unbound Unbound Unbound Unbound Unbound
2ivsB02 Unbound Unbound Unbound Unbound Unbound
2ivtA02 Unbound Unbound Unbound Unbound Unbound
2ivuA02 Unbound Unbound Unbound Unbound Unbound
2ivvA02 Unbound Unbound Unbound Unbound Unbound
2x2kA02 Unbound Unbound Unbound Unbound Unbound
2x2lA02 Unbound Unbound Unbound Unbound Unbound
2x2mA02 Unbound Unbound Unbound Unbound Unbound
2x2mB02 Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Swiss-prot;P07949

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
2x2uA01
2x2uA02
2ivsA01
2ivsB01
2ivtA01 invisible 712-714
2ivuA01 invisible 713
2ivvA01 invisible 712-715
2x2kA01 invisible 712-714
2x2lA01 invisible 713-714
2x2mA01 invisible 713
2x2mB01 invisible 712-714
2ivsA02 ASP 874;ARG 878 ASN 879;ASP 892 (Magnesium binding) TYR 905 (auto-phosphorylation) invisible 828-843
2ivsB02 ASP 874;ARG 878 ASN 879;ASP 892 (Magnesium binding) (auto-phosphorylation) invisible 822-843, 900-910
2ivtA02 ASP 874;ARG 878 ASN 879;ASP 892 (Magnesium binding) PTR 905 (auto-phosphorylation) invisible 823-843
2ivuA02 ASP 874;ARG 878 ASN 879;ASP 892 (Magnesium binding) PTR 905 (auto-phosphorylation) invisible 821-843
2ivvA02 ASP 874;ARG 878 ASN 879;ASP 892 (Magnesium binding) PTR 905 (auto-phosphorylation) invisible 821-845
2x2kA02 ASP 874;ARG 878 ASN 879;ASP 892 (Magnesium binding) PTR 905 (auto-phosphorylation) invisible 823-843
2x2lA02 ASP 874;ARG 878 ASN 879;ASP 892 (Magnesium binding) PTR 905 (auto-phosphorylation) invisible 823-843
2x2mA02 ASP 874;ARG 878 ASN 879;ASP 892 (Magnesium binding) PTR 905 (auto-phosphorylation) invisible 821-844
2x2mB02 ASP 874;ARG 878 ASN 879;ASP 892 (Magnesium binding) PTR 905 (auto-phosphorylation) invisible 820-844

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[12]
Figure 5

References
[1]
Resource
Comments
Medline ID
PubMed ID 8674117
Journal Cell
Year 1996
Volume 85
Pages 1113-24
Authors Jing S, Wen D, Yu Y, Holst PL, Luo Y, Fang M, Tamir R, Antonio L, Hu Z, Cupples R, Louis JC, Hu S, Altrock BW, Fox GM
Title GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 8657309
Journal Nature
Year 1996
Volume 382
Pages 80-3
Authors Treanor JJ, Goodman L, de Sauvage F, Stone DM, Poulsen KT, Beck CD, Gray C, Armanini MP, Pollock RA, Hefti F, Phillips HS, Goddard A, Moore MW, Buj-Bello A, Davies AM, Asai N, Takahashi M, Vandlen R, Henderson CE, Rosenthal A
Title Characterization of a multicomponent receptor for GDNF.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 9192898
Journal Nature
Year 1997
Volume 387
Pages 717-21
Authors Klein RD, Sherman D, Ho WH, Stone D, Bennett GL, Moffat B, Vandlen R, Simmons L, Gu Q, Hongo JA, Devaux B, Poulsen K, Armanini M, Nozaki C, Asai N, Goddard A, Phillips H, Henderson CE, Takahashi M, Rosenthal A
Title A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 9467954
Journal Oncogene
Year 1998
Volume 16
Pages 293-9
Authors Nozaki C, Asai N, Murakami H, Iwashita T, Iwata Y, Horibe K, Klein RD, Rosenthal A, Takahashi M
Title Calcium-dependent Ret activation by GDNF and neurturin.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 10545102
Journal EMBO J
Year 1999
Volume 18
Pages 5901-10
Authors Eketjall S, Fainzilber M, Murray-Rust J, Ibanez CF
Title Distinct structural elements in GDNF mediate binding to GFRalpha1 and activation of the GFRalpha1-c-Ret receptor complex.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 11445581
Journal J Biol Chem
Year 2001
Volume 276
Pages 35808-17
Authors Anders J, Kjar S, Ibanez CF
Title Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 11988777
Journal Nat Rev Neurosci
Year 2002
Volume 3
Pages 383-94
Authors Airaksinen MS, Saarma M
Title The GDNF family: signalling, biological functions and therapeutic value.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 14514671
Journal J Biol Chem
Year 2003
Volume 278
Pages 47898-904
Authors Kjaer S, Ibanez CF
Title Identification of a surface for binding to the GDNF-GFR alpha 1 complex in the first cadherin-like domain of RET.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 15044950
Journal EMBO J
Year 2004
Volume 23
Pages 1452-62
Authors Leppanen VM, Bespalov MM, Runeberg-Roos P, Puurand U, Merits A, Saarma M, Goldman A
Title The structure of GFRalpha1 domain 3 reveals new insights into GDNF binding and RET activation.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 15722196
Journal Cell Signal
Year 2005
Volume 17
Pages 717-27
Authors Amoresano A, Incoronato M, Monti G, Pucci P, de Franciscis V, Cerchia L
Title Direct interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex.
Related PDB
Related UniProtKB
[11]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 705-1013 ALONE AND IN COMPLEX WITH INHIBITORS, MASS SPECTROMETRY, PHOSPHORYLATION AT TYR-900 AND TYR-905.
Medline ID
PubMed ID 16928683
Journal J Biol Chem
Year 2006
Volume 281
Pages 33577-87
Authors Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, Ibanez CF, McDonald NQ
Title Structure and chemical inhibition of the RET tyrosine kinase domain.
Related PDB 2ivs 2ivt 2ivu 2ivv
Related UniProtKB P07949
[12]
Resource
Comments
Medline ID
PubMed ID 17013378
Journal Nat Chem Biol
Year 2006
Volume 2
Pages 636-44
Authors Schlee S, Carmillo P, Whitty A
Title Quantitative analysis of the activation mechanism of the multicomponent growth-factor receptor Ret.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 16765900
Journal Structure
Year 2006
Volume 14
Pages 1083-92
Authors Wang X, Baloh RH, Milbrandt J, Garcia KC
Title Structure of artemin complexed with its receptor GFRalpha3: convergent recognition of glial cell line-derived neurotrophic factors.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 17218019
Journal Trends Pharmacol Sci
Year 2007
Volume 28
Pages 68-74
Authors Bespalov MM, Saarma M
Title GDNF family receptor complexes are emerging drug targets.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 18845535
Journal J Biol Chem
Year 2008
Volume 283
Pages 35164-72
Authors Parkash V, Leppanen VM, Virtanen H, Jurvansuu JM, Bespalov MM, Sidorova YA, Runeberg-Roos P, Saarma M, Goldman A
Title The structure of the glial cell line-derived neurotrophic factor-coreceptor complex: insights into RET signaling and heparin binding.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 20117004
Journal Bioorg Med Chem
Year 2010
Volume 18
Pages 1482-96
Authors Mologni L, Rostagno R, Brussolo S, Knowles PP, Kjaer S, Murray-Rust J, Rosso E, Zambon A, Scapozza L, McDonald NQ, Lucchini V, Gambacorti-Passerini C
Title Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.
Related PDB 2x2k 2x2l 2x2m
Related UniProtKB P07949
[17]
Resource
Comments
Medline ID
PubMed ID 20473317
Journal Nat Struct Mol Biol
Year 2010
Volume 17
Pages 726-31
Authors Kjaer S, Hanrahan S, Totty N, McDonald NQ
Title Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations.
Related PDB 2x2u
Related UniProtKB P07949

Comments
This enzyme belongs to receptor tyrosine kinase family.
This enzyme consists of the N-terminal extracellular region, the transmembrane region, and the C-terminal intracellular region (see [7] and [11]). The extracellular region is composed of four N-terminal cadherin-like domains followed by a cysteine-rich domain (see [6], [7] and [11]). On the other hand, the intracellular region is composed of a juxtamembrane domain, a kinase domain, and a tail region (see [7] and [11]).
The catalytic domain of this enzyme is homologous to that of vascular endothelial growth factor receptor (M00131 in EzCatDB).
According to the literature [7], [8], [10] and [11], this enzyme is activated by binding to a complex of a glial cell line-derived neutrophic factor (GDNF) family ligand and its cognate receptor, the GDNF family receptor alpha (GFRalpha).
The GDNF family ligands, including GDNF, neurturin (NRTN), artemin (ARTN) and persephin (PSPN), are homologous to the transforming growth factor-beta (TGF-beta) (see [7]). GFRalpha1 binds preferentially to GDNF, GFRalpha2 to NRTN, GFRalpha3 to ARTN, and GFRalpha4 to PSPN (see [7] and [13]). These receptor complexes with this enzyme can be drug targets (see [14]).
According to the literature[11], autophosphorylation of Tyr905 on A-loop is not required for RET catalytic activity.

Created Updated
2011-10-26 2012-12-21