DB code: T00221

RLCP classification	1.15.36030.52 : Hydrolysis
CATH domain	3.30.505.10 : SHC Adaptor Protein
	3.30.505.10 : SHC Adaptor Protein
	3.90.190.10 : Protein-Tyrosine Phosphatase; Chain A	Catalytic domain
E.C.	3.1.3.48
CSA
M-CSA
MACiE

CATH domain	Related DB codes (homologues)
3.30.505.10 : SHC Adaptor Protein	M00183 M00043 M00130 M00148 T00256 M00304 M00333 M00339 M00344
3.90.190.10 : Protein-Tyrosine Phosphatase; Chain A	M00169 S00458 D00154 M00149

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	RefSeq	Pfam
Q06124	Tyrosine-protein phosphatase non-receptor type 11	EC 3.1.3.48 Protein-tyrosine phosphatase 2C PTP-2C PTP-1D SH-PTP3 SH-PTP2 SHP-2 Shp2	NP_002825.3 (Protein) NM_002834.3 (DNA/RNA sequence) NP_542168.1 (Protein) NM_080601.1 (DNA/RNA sequence)	PF00017 (SH2) PF00102 (Y_phosphatase) [Graphical View]

KEGG enzyme name
protein-tyrosine-phosphatase phosphotyrosine phosphatase phosphoprotein phosphatase (phosphotyrosine) phosphotyrosine histone phosphatase protein phosphotyrosine phosphatase tyrosylprotein phosphatase phosphotyrosine protein phosphatase phosphotyrosylprotein phosphatase tyrosine O-phosphate phosphatase PPT-phosphatase PTPase [phosphotyrosine]protein phosphatase PTP-phosphatase

UniprotKB: Accession Number	Entry name	Activity	Subunit	Subcellular location	Cofactor
Q06124	PTN11_HUMAN	Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate.	Interacts with phosphorylated LIME1 and BCAR3. Interacts with SHB and INPP5D/SHIP1 (By similarity). Interacts with PTPNS1 and CD84. Interacts with phosphorylated SIT1 and MPZL1. Interacts with FCRL3, FCRL4, FCRL6 and ANKHD1.	Cytoplasm.

KEGG Pathways
Map code	Pathways	E.C.

Compound table
	Substrates		Products		Intermediates
KEGG-id	C01167	C00001	C00585	C00009
E.C.
Compound	Protein tyrosine phosphate	H2O	Protein tyrosine	Orthophosphate
Type	aromatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion	H2O	aromatic ring (only carbon atom),peptide/protein	phosphate group/phosphate ion
ChEBI		15377 15377		26078 26078
PubChem		22247451 962 22247451 962		1004 22486802 1004 22486802

2shpA01	Unbound		Unbound	Unbound
2shpB01	Unbound		Unbound	Unbound
2shpA02	Unbound		Unbound	Unbound
2shpB02	Unbound		Unbound	Unbound
2shpA03	Unbound		Unbound	Unbound
2shpB03	Unbound		Unbound	Unbound

Reference for Active-site residues
resource	references	E.C.
Swiss-prot;Q06124 & literature [10]

Active-site residues
PDB	Catalytic residues	Cofactor-binding residues	Modified residues	Main-chain involved in catalysis	Comment

2shpA01					mutant T2K, F41L
2shpB01					mutant T2K, F41L
2shpA02
2shpB02
2shpA03	ASP 425;CYS 459;ARG 465;THR 466		; (phospholylated)	SER 460;ALA 461;ILE 463;GLY 464;ARG 465	mutant F513S, deletion 528-593, phosphorylated Y542/Y580
2shpB03	ASP 425;CYS 459;ARG 465;THR 466		; (phospholylated)	SER 460;ALA 461;ILE 463;GLY 464;ARG 465	mutant F513S, deletion 528-593, phosphorylated Y542/Y580

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[9]	p.422-444
[10]	Fig.3, p.635-638

References
[1]
Resource
Comments	PHOSPHORYLATION BY PDGFR.
Medline ID	94316690
PubMed ID	8041791
Journal	Proc Natl Acad Sci U S A
Year	1994
Volume	91
Pages	7335-9
Authors	Bennett AM, Tang TL, Sugimoto S, Walsh CT, Neel BG
Title	Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras.
Related PDB
Related UniProtKB	Q06124
[2]
Resource
Comments
Medline ID
PubMed ID	7521735
Journal	Structure
Year	1994
Volume	2
Pages	423-38
Authors	Lee CH, Kominos D, Jacques S, Margolis B, Schlessinger J, Shoelson SE, Kuriyan J
Title	Crystal structures of peptide complexes of the amino-terminal SH2 domain of the Syp tyrosine phosphatase.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID	8895367
Journal	Endocrinology
Year	1996
Volume	137
Pages	4944-52
Authors	Rocchi S, Tartare-Deckert S, Sawka-Verhelle D, Gamha A, van Obberghen E
Title	Interaction of SH2-containing protein tyrosine phosphatase 2 with the insulin receptor and the insulin-like growth factor-I receptor: studies of the domains involved using the yeast two-hybrid system.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID	8647120
Journal	Eur J Biochem
Year	1996
Volume	237
Pages	736-42
Authors	Tailor P, Jascur T, Williams S, von Willebrand M, Couture C, Mustelin T
Title	Involvement of Src-homology-2-domain-containing protein-tyrosine phosphatase 2 in T cell activation.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID	9195950
Journal	J Biol Chem
Year	1997
Volume	272
Pages	16421-30
Authors	Gu H, Griffin JD, Neel BG
Title	Characterization of two SHP-2-associated binding proteins and potential substrates in hematopoietic cells.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID	9312087
Journal	J Biol Chem
Year	1997
Volume	272
Pages	24868-75
Authors	Jackson DE, Kupcho KR, Newman PJ
Title	Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of platelet/endothelial cell adhesion molecule-1 (PECAM-1) that are required for the cellular association and activation of the protein-tyrosine phosphatase, SHP-2.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID	9038217
Journal	J Biol Chem
Year	1997
Volume	272
Pages	5966-73
Authors	Tenev T, Keilhack H, Tomic S, Stoyanov B, Stein-Gerlach M, Lammers R, Krivtsov AV, Ullrich A, Bohmer FD
Title	Both SH2 domains are involved in interaction of SHP-1 with the epidermal growth factor receptor but cannot confer receptor-directed activity to SHP-1/SHP-2 chimera.
Related PDB
Related UniProtKB
[8]
Resource
Comments	INTERACTION WITH PTPNS1.
Medline ID	97215901
PubMed ID	9062191
Journal	Nature
Year	1997
Volume	386
Pages	181-6
Authors	Kharitonenkov A, Chen Z, Sures I, Wang H, Schilling J, Ullrich A
Title	A family of proteins that inhibit signalling through tyrosine kinase receptors.
Related PDB
Related UniProtKB	Q06124
[9]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-526.
Medline ID	98150850
PubMed ID	9491886
Journal	Cell
Year	1998
Volume	92
Pages	441-50
Authors	Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE
Title	Crystal structure of the tyrosine phosphatase SHP-2.
Related PDB	2shp
Related UniProtKB	Q06124
[10]
Resource
Comments
Medline ID
PubMed ID	9818190
Journal	Curr Opin Chem Biol
Year	1998
Volume	2
Pages	633-41
Authors	Denu JM, Dixon JE
Title	Protein tyrosine phosphatases: mechanisms of catalysis and regulation.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID	9693956
Journal	Int J Biochem Cell Biol
Year	1998
Volume	30
Pages	559-66
Authors	Stein-Gerlach M, Wallasch C, Ullrich A
Title	SHP-2, SH2-containing protein tyrosine phosphatase-2.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID	9660791
Journal	J Biol Chem
Year	1998
Volume	273
Pages	18273-81
Authors	Gesbert F, Guenzi C, Bertoglio J
Title	A new tyrosine-phosphorylated 97-kDa adaptor protein mediates interleukin-2-induced association of SHP-2 with p85-phosphatidylinositol 3-kinase in human T lymphocytes.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID	9535915
Journal	J Biol Chem
Year	1998
Volume	273
Pages	9234-42
Authors	Takada T, Matozaki T, Takeda H, Fukunaga K, Noguchi T, Fujioka Y, Okazaki I, Tsuda M, Yamao T, Ochi F, Kasuga M
Title	Roles of the complex formation of SHPS-1 with SHP-2 in insulin-stimulated mitogen-activated protein kinase activation.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID	9600917
Journal	Proc Natl Acad Sci U S A
Year	1998
Volume	95
Pages	6061-6
Authors	Carpenter LR, Farruggella TJ, Symes A, Karow ML, Yancopoulos GD, Stahl N
Title	Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID	9695189
Journal	Semin Immunol
Year	1998
Volume	10
Pages	329-47
Authors	Siminovitch KA, Neel BG
Title	Regulation of B cell signal transduction by SH2-containing protein-tyrosine phosphatases.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID	9551546
Journal	Structure
Year	1998
Volume	6
Pages	249-54
Authors	Barford D, Neel BG
Title	Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2.
Related PDB
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID	9931295
Journal	Biochem J
Year	1999
Volume	338
Pages	35-9
Authors	Zhao R, Zhao ZJ
Title	Tyrosine phosphatase SHP-2 dephosphorylates the platelet-derived growth factor receptor but enhances its downstream signalling.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID	10074424
Journal	Curr Biol
Year	1999
Volume	9
Pages	R129-32
Authors	Huyer G, Alexander DR
Title	Immune signalling: SHP-2 docks at multiple ports.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID	10579910
Journal	Exp Cell Res
Year	1999
Volume	253
Pages	47-54
Authors	Feng GS
Title	Shp-2 tyrosine phosphatase: signaling one cell or many.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID	10781410
Journal	Curr Opin Immunol
Year	2000
Volume	12
Pages	307-15
Authors	Tamir I, Dal Porto JM, Cambier JC
Title	Cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2: regulators of B cell signal transduction.
Related PDB
Related UniProtKB
[21]
Resource
Comments
Medline ID
PubMed ID	10681522
Journal	J Biol Chem
Year	2000
Volume	275
Pages	5453-9
Authors	Zhao R, Zhao ZJ
Title	Dissecting the interaction of SHP-2 with PZR, an immunoglobulin family protein containing immunoreceptor tyrosine-based inhibitory motifs.
Related PDB
Related UniProtKB
[22]
Resource
Comments
Medline ID
PubMed ID	12421673
Journal	Biochim Biophys Acta
Year	2002
Volume	1592
Pages	297-301
Authors	Qu CK
Title	Role of the SHP-2 tyrosine phosphatase in cytokine-induced signaling and cellular response.
Related PDB
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID	12731888
Journal	Biochemistry
Year	2003
Volume	42
Pages	5461-8
Authors	Lu W, Shen K, Cole PA
Title	Chemical dissection of the effects of tyrosine phosphorylation of SHP-2.
Related PDB
Related UniProtKB
[24]
Resource
Comments
Medline ID
PubMed ID	12707331
Journal	J Immunol
Year	2003
Volume	170
Pages	4539-47
Authors	Yusa S, Campbell KS
Title	Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) can play a direct role in the inhibitory function of killer cell Ig-like receptors in human NK cells.
Related PDB
Related UniProtKB

Comments
This enzyme is composed of two SH2 domains, and the C-terminal catalytic domain. According to the literature [9], the N-terminal SH2 domain seems to inhibit the catalytic reaction by interacting directly with the active site. As the catalytic domain is homologous to other phosphatase domains (S00458, D00154, M00149, M00169 in EzCatDB) and the catalytic residues are conserved, the mechanism must be similar to those of the counterparts. The literature [10] confirmed that Cys459, Asp425 and Arg465 act as nucleophile, acid-base, and stabilizer for the phosphate group, respectively, and that loop 460-465 also stabilizes the phosphate group during the catalysis.

Comments

This enzyme is composed of two SH2 domains, and the C-terminal catalytic domain. According to the literature [9], the N-terminal SH2 domain seems to inhibit the catalytic reaction by interacting directly with the active site.
As the catalytic domain is homologous to other phosphatase domains (S00458, D00154, M00149, M00169 in EzCatDB) and the catalytic residues are conserved, the mechanism must be similar to those of the counterparts. The literature [10] confirmed that Cys459, Asp425 and Arg465 act as nucleophile, acid-base, and stabilizer for the phosphate group, respectively, and that loop 460-465 also stabilizes the phosphate group during the catalysis.

Created	Updated
2005-03-08	2009-02-26