DB code: M00339

RLCP classification 3.103.130000.1162 : Transfer
CATH domain 1.-.-.- :
1.-.-.- :
3.30.505.10 : SHC Adaptor Protein
3.30.200.20 : Phosphorylase Kinase; domain 1
1.10.510.10 : Transferase(Phosphotransferase); domain 1 Catalytic domain
E.C. 2.7.10.2
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 M00326 M00327 M00328 M00329 M00330 M00331 M00332 M00333 M00335 M00344
3.30.200.20 : Phosphorylase Kinase; domain 1 M00125 M00124 M00131 T00224 M00127 M00129 M00130 M00132 M00136 M00196 M00197 M00198 M00304 M00323 M00325 M00326 M00327 M00328 M00329 M00330 M00331 M00332 M00333 M00335 M00344 D00298
3.30.505.10 : SHC Adaptor Protein M00183 M00043 M00130 M00148 T00256 M00304 M00333 M00344 T00221

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P07332 Tyrosine-protein kinase Fes/Fps
EC 2.7.10.2
Feline sarcoma/Fujinami avian sarcoma oncogene homolog
Proto-oncogene c-Fes
Proto-oncogene c-Fps
p93c-fes
NP_001137255.1 (Protein)
NM_001143783.1 (DNA/RNA sequence)
NP_001137256.1 (Protein)
NM_001143784.1 (DNA/RNA sequence)
NP_001137257.1 (Protein)
NM_001143785.1 (DNA/RNA sequence)
NP_001996.1 (Protein)
NM_002005.3 (DNA/RNA sequence)
PF00611 (FCH)
PF07714 (Pkinase_Tyr)
PF00017 (SH2)
[Graphical View]

KEGG enzyme name
Non-specific protein-tyrosine kinase
ATP:protein-tyrosine O-phosphotransferase (ambiguous)
Cytoplasmic protein tyrosine kinase
FER
FES
FPS
Protein-tyrosine kinase (ambiguous)

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P07332 FES_HUMAN ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Homooligomer. Interacts with BCR. Interacts (when activated, via coiled coil domain) with TRIM28. Interacts (via SH2 domain) with phosphorylated EZR, MS4A2/FCER1B and HCLS1/HS1. Interacts with phosphorylated KIT. Interacts with FLT3. Interacts (via FCH domain) with soluble tubulin. Interacts (via SH2 domain) with microtubules. Cytoplasm > cytosol. Cytoplasm > cytoskeleton. Cell membrane, Peripheral membrane protein, Cytoplasmic side. Cytoplasmic vesicle. Golgi apparatus. Cell junction > focal adhesion. Note: Distributed throughout the cytosol when the kinase is not activated. Association with microtubules requires activation of the kinase activity. Shuttles between focal adhesions and cell-cell contacts in epithelial cells. Recruited to the lateral cell membrane in polarized epithelial cells by interaction with phosphorylated EZR. Detected at tubular membrane structures in the cytoplasm and at the cell periphery.

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
15422
16761
PubChem 888
5957
6022
4dylA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
4dylA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1wquA00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
2dcrA00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3bkbA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3cblA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3cd3A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
4e93A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3bkbA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3cblA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3cd3A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
4e93A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3bkbA03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3cblA03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Analogue:ACE-ILE-TYR-GLU-SER-LEU (chain B) Unbound Unbound
3cd3A03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Analogue:ACE-ILE-TYR-GLU-SER-LEU (chain B) Unbound Unbound
4e93A03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Literature [11]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
4dylA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
4dylA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1wquA00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
2dcrA00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
3bkbA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
3cblA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
3cd3A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
4e93A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
3bkbA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
3cblA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 487-488, 496-500, 516-519, 538-542
3cd3A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 486-488, 496-500, 507-510, 516-519, 538-540
4e93A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 487-488
3bkbA03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 683;ARG 687 ASN 688;ASP 701 TYR 713(auto-phosphorylation)
3cblA03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 683;ARG 687 ASN 688;ASP 701 TYR 713(auto-phosphorylation)
3cd3A03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 683;ARG 687 ASN 688;ASP 701 PTR 713(auto-phosphorylation)
4e93A03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 683;ARG 687 ASN 688;ASP 701 invisible 708-721

References for Catalytic Mechanism
References Sections No. of steps in catalysis

References
[1]
Resource
Comments
Medline ID
PubMed ID 8334128
Journal Biochemistry
Year 1993
Volume 32
Pages 6995-7001
Authors Fang F, Ahmad S, Lei J, Klecker RW, Trepel JB, Smithgall TE, Glazer RI
Title Effect of the mutation of tyrosine 713 in p93c-fes on its catalytic activity and ability to promote myeloid differentiation in K562 cells.
Related PDB
Related UniProtKB
[2]
Resource
Comments PHOSPHORYLATION AT TYR-713, CATALYTIC ACTIVITY, MUTAGENESIS OF TYR-713.
Medline ID
PubMed ID 7687763
Journal Oncogene
Year 1993
Volume 8
Pages 2283-92
Authors Hjermstad SJ, Peters KL, Briggs SD, Glazer RI, Smithgall TE
Title Regulation of the human c-fes protein tyrosine kinase (p93c-fes) by its src homology 2 domain and major autophosphorylation site (Tyr-713).
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 8663427
Journal J Biol Chem
Year 1996
Volume 271
Pages 17519-25
Authors Rogers JA, Read RD, Li J, Peters KL, Smithgall TE
Title Autophosphorylation of the Fes tyrosine kinase. Evidence for an intermolecular mechanism involving two kinase domain tyrosine residues.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 9218495
Journal J Biol Chem
Year 1997
Volume 272
Pages 18498-503
Authors Read RD, Lionberger JM, Smithgall TE
Title Oligomerization of the Fes tyrosine kinase. Evidence for a coiled-coil domain in the unique N-terminal region.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 10567558
Journal Mol Cell Biol
Year 1999
Volume 19
Pages 8335-43
Authors Cheng H, Rogers JA, Dunham NA, Smithgall TE
Title Regulation of c-Fes tyrosine kinase and biological activities by N-terminal coiled-coil oligomerization domains.
Related PDB
Related UniProtKB
[6]
Resource
Comments FUNCTION IN CELL PROLIFERATION AND CELL SPREADING, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, SUBUNIT, DOMAIN, MUTAGENESIS OF LEU-145 AND LEU-334.
Medline ID
PubMed ID 11509660
Journal Mol Cell Biol
Year 2001
Volume 21
Pages 6170-80
Authors Cheng HY, Schiavone AP, Smithgall TE
Title A point mutation in the N-terminal coiled-coil domain releases c-Fes tyrosine kinase activity and survival signaling in myeloid leukemia cells.
Related PDB
Related UniProtKB
[7]
Resource
Comments REVIEW.
Medline ID
PubMed ID 11994747
Journal Nat Rev Mol Cell Biol
Year 2002
Volume 3
Pages 278-89
Authors Greer P
Title Closing in on the biological functions of Fps/Fes and Fer.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 12653561
Journal Biochemistry
Year 2003
Volume 42
Pages 3567-74
Authors Takashima Y, Delfino FJ, Engen JR, Superti-Furga G, Smithgall TE
Title Regulation of c-Fes tyrosine kinase activity by coiled-coil and SH2 domains: analysis with Saccharomyces cerevisiae.
Related PDB
Related UniProtKB
[9]
Resource
Comments STRUCTURE BY NMR OF 450-550.
Medline ID
PubMed ID 15929003
Journal J Biomol NMR
Year 2005
Volume 31
Pages 357-61
Authors Scott A, Pantoja-Uceda D, Koshiba S, Inoue M, Kigawa T, Terada T, Shirouzu M, Tanaka A, Sugano S, Yokoyama S, Guntert P
Title Solution structure of the Src homology 2 domain from the human feline sarcoma oncogene Fes.
Related PDB 1wqu
Related UniProtKB P07332
[10]
Resource
Comments
Medline ID
PubMed ID 17017791
Journal J Am Chem Soc
Year 2006
Volume 128
Pages 13112-22
Authors Lopez-Mendez B, Guntert P
Title Automated protein structure determination from NMR spectra.
Related PDB 2dcr
Related UniProtKB P07332
[11]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.78 ANGSTROMS) OF 448-822 OF UNPHOSPHORYLATED APOPROTEIN AND IN COMPLEX WITH STAUROSPORINE AND A SUBSTRATE PEPTIDE, CATALYTIC ACTIVITY, ENZYME REGULATION, PHOSPHORYLATION AT TYR-713, NMR SPECTROSCOPY, MUTAGENESIS OF GLY-463 AND ARG-483.
Medline ID
PubMed ID 18775312
Journal Cell
Year 2008
Volume 134
Pages 793-803
Authors Filippakopoulos P, Kofler M, Hantschel O, Gish GD, Grebien F, Salah E, Neudecker P, Kay LE, Turk BE, Superti-Furga G, Pawson T, Knapp S
Title Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.
Related PDB 3bkb 3cbl 3cd3
Related UniProtKB P07332
[12]
Resource
Comments SUBUNIT, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYR-713, PHOSPHORYLATION BY HCK, DOMAIN.
Medline ID
PubMed ID 19382747
Journal Biochemistry
Year 2009
Volume 48
Pages 4780-8
Authors Shaffer JM, Hellwig S, Smithgall TE
Title Bimolecular fluorescence complementation demonstrates that the c-Fes protein-tyrosine kinase forms constitutive oligomers in living cells.
Related PDB
Related UniProtKB
[13]
Resource
Comments FUNCTION, INTERACTION WITH MS4A2/FCER1B AND HCLS1/HS1, SUBCELLULAR LOCATION, PHOSPHORYLATION, INTERACTION WITH PHOSPHOINOSITIDE-CONTAINING MEMBRANES, MUTAGENESIS OF 113-ARG-LYS-114.
Medline ID
PubMed ID 19001085
Journal Mol Cell Biol
Year 2009
Volume 29
Pages 389-401
Authors McPherson VA, Everingham S, Karisch R, Smith JA, Udell CM, Zheng J, Jia Z, Craig AW
Title Contributions of F-BAR and SH2 domains of Fes protein tyrosine kinase for coupling to the FcepsilonRI pathway in mast cells.
Related PDB
Related UniProtKB
[14]
Resource
Comments REVIEW.
Medline ID
PubMed ID 21622225
Journal Front Biosci
Year 2011
Volume 17
Pages 3146-55
Authors Hellwig S, Smithgall TE
Title Structure and regulation of the c-Fes protein-tyrosine kinase.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 22201778
Journal Front Biosci
Year 2012
Volume 17
Pages 861-75
Authors Craig AW
Title FES/FER kinase signaling in hematopoietic cells and leukemias.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 22520759
Journal Chem Biol
Year 2012
Volume 19
Pages 529-40
Authors Hellwig S, Miduturu CV, Kanda S, Zhang J, Filippakopoulos P, Salah E, Deng X, Choi HG, Zhou W, Hur W, Knapp S, Gray NS, Smithgall TE
Title Small-molecule inhibitors of the c-Fes protein-tyrosine kinase.
Related PDB 4e93
Related UniProtKB

Comments
This enzyme belongs to Fes/Fps subfamily of nonreceptor protein tyrosine kinases. (Fes indicates feline sarcoma, whereas Fps indicates Fujinami poultry sarcoma.) This enzyme is a proto-oncogene product.
This enzyme is composed of N-terminal F-BAR domain, FX domain, Src homology 2 (SH2) domain, and C-terminal kinase domain.
The catalytic domain of this enzyme is homologous to that of proto-oncogene tyrosine-protein kinase ABL1 (M00130 in EzCatDB).
The N-terminal F-BAR domain must be necessary for oligomerization of this enzyme (see [4] and [15]).
The SH2 domain can enhance the catalytic activity and substrate recognition of the kinase domain (see [11]). According to the literature [11], binding of a phosphorylated ligand to the SH2 domain can stabilize the interaction between the SH2 domain and the kinase domain.
Autophosphorylation of Tyr713 in the kinase domain stimulates the catalytic activity (see [2]). According to the literature [11], phosphorylation of activation segment at Tyr713 and binding of substrate molecule to the linase domain stabilize the conformation of active site suitable for catalysis.

Created Updated
2012-06-25 2012-12-18