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 18420	15422 15422		16761 16761
PubChem	888 888	5957 5957		6022 6022

4dylA01	Unbound	Unbound	Unbound	Unbound	Unbound
4dylA02	Unbound	Unbound	Unbound	Unbound	Unbound
1wquA00	Unbound	Unbound	Unbound	Unbound	Unbound
2dcrA00	Unbound	Unbound	Unbound	Unbound	Unbound
3bkbA01	Unbound	Unbound	Unbound	Unbound	Unbound
3cblA01	Unbound	Unbound	Unbound	Unbound	Unbound
3cd3A01	Unbound	Unbound	Unbound	Unbound	Unbound
4e93A01	Unbound	Unbound	Unbound	Unbound	Unbound
3bkbA02	Unbound	Unbound	Unbound	Unbound	Unbound
3cblA02	Unbound	Unbound	Unbound	Unbound	Unbound
3cd3A02	Unbound	Unbound	Unbound	Unbound	Unbound
4e93A02	Unbound	Unbound	Unbound	Unbound	Unbound
3bkbA03	Unbound	Unbound	Unbound	Unbound	Unbound
3cblA03	Unbound	Unbound	Analogue:ACE-ILE-TYR-GLU-SER-LEU (chain B)	Unbound	Unbound
3cd3A03	Unbound	Unbound	Analogue:ACE-ILE-TYR-GLU-SER-LEU (chain B)	Unbound	Unbound
4e93A03	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
4dylA02
1wquA00
2dcrA00
3bkbA01
3cblA01
3cd3A01
4e93A01
3bkbA02
3cblA02					invisible 487-488, 496-500, 516-519, 538-542
3cd3A02					invisible 486-488, 496-500, 507-510, 516-519, 538-540
4e93A02					invisible 487-488
3bkbA03	ASP 683;ARG 687	ASN 688;ASP 701	TYR 713(auto-phosphorylation)
3cblA03	ASP 683;ARG 687	ASN 688;ASP 701	TYR 713(auto-phosphorylation)
3cd3A03	ASP 683;ARG 687	ASN 688;ASP 701	PTR 713(auto-phosphorylation)
4e93A03	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.

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