Protein tyrosine phosphatase

Protein-tyrosine-phosphatase
Protein tyrosine phosphatase 1, trimer, Human
Identifiers
EC no.	3.1.3.48
CAS no.	79747-53-8
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Search PMC articles PubMed articles NCBI proteins

Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins:

[a protein]-tyrosine phosphate + H₂O = [a protein]-tyrosine + phosphate

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular localization, affect protein stability, and regulate enzyme activity. As a consequence, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase; EC 3.1.3.48) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation, transformation, and synaptic plasticity.^[1][2][3][4]

Together with tyrosine kinases, PTPs regulate the phosphorylation state of many important signalling molecules, such as the MAP kinase family. PTPs are increasingly viewed as integral components of signal transduction cascades, despite less study and understanding compared to tyrosine kinases.

PTPs have been implicated in regulation of many cellular processes, including, but not limited to:

• Cell growth
• Cellular differentiation
• Mitotic cycles
• Oncogenic transformation
• Receptor endocytosis^[5]

PTP activity can be found in four protein families.^[6][7]

Links to all 107 members of the protein tyrosine phosphatase family can be found in the template at the bottom of this article.

The class I PTPs, are the largest group of PTPs with 99 members, which can be further subdivided into

• 38 classical PTPs
  • 21 receptor tyrosine phosphatases
  • 17 nonreceptor-type PTPs
• 61 VH-1-like or dual-specific phosphatases (DSPs)
  • 11 MAPK phosphatases (MPKs)
  • 3 Slingshots
  • 3 PRLs
  • 4 CDC14s
  • 19 atypical DSPs
  • 5 phosphatase and tensin homologs (PTENs)
  • 16 myotubularins

Dual-specificity phosphatases (dTyr and dSer/dThr) dual-specificity protein-tyrosine phosphatases. Ser/Thr and Tyr dual-specificity phosphatases are a group of enzymes with both Ser/Thr (EC 3.1.3.16) and tyrosine-specific protein phosphatase (EC 3.1.3.48) activity able to remove the serine/threonine or the tyrosine-bound phosphate group from a wide range of phosphoproteins, including a number of enzymes that have been phosphorylated under the action of a kinase. Dual-specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle.

LEOPARD syndrome, Noonan syndrome, and metachondromatosis are associated with PTPN11.

Elevated levels of activated PTPN5 negatively affects synaptic stability and plays a role in Alzheimer's disease,^[3] Fragile X syndrome,^[4] schizophrenia,^[8] and Parkinson's disease.^[9] Decreased levels of PTPN5 has been implicated in Huntington's disease,^[10][11] brain ischemia,^[12] alcohol use disorder,^[13][14] and stress disorders.^[15][16] Together these findings indicate that only at optimal levels of PTPN5 is synaptic function unimpaired.

LMW (low-molecular-weight) phosphatases, or acid phosphatases, act on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates.^[17][18]

The class II PTPs contain only one member, low-molecular-weight phosphotyrosine phosphatase (LMPTP).

Cdc25 phosphatases (dTyr and/or dThr)

The Class III PTPs contains three members, CDC25 A, B, and C

These are members of the HAD fold and superfamily, and include phosphatases specific to pTyr and pSer/Thr as well as small molecule phosphatases and other enzymes.^[19] The subfamily EYA (eyes absent) is believed to be pTyr-specific, and has four members in human, EYA1, EYA2, EYA3, and EYA4. This class has a distinct catalytic mechanism from the other three classes.^[20]

Based on their cellular localization, PTPases are also classified as:

• Receptor-like, which are transmembrane receptors that contain PTPase domains.^[21] In terms of structure, all known receptor PTPases are made up of a variable-length extracellular domain, followed by a transmembrane region and a C-terminal catalytic cytoplasmic domain. Some of the receptor PTPases contain fibronectin type III (FN-III) repeats, immunoglobulin-like domains, MAM domains, or carbonic anhydrase-like domains in their extracellular region. In general, the cytoplasmic region contains two copies of the PTPase domain. The first seems to have enzymatic activity, whereas the second is inactive.
• Non-receptor (intracellular) PTPases^[22]

All PTPases, other than those of the EYA family, carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and possess a similar core structure made of a central parallel beta-sheet with flanking alpha-helices containing a beta-loop-alpha-loop that encompasses the PTP signature motif.^[23] Functional diversity between PTPases is endowed by regulatory domains and subunits.

Low-molecular-weight phosphotyrosine protein phosphatase Structure of a low-molecular-weight phosphotyrosine protein phosphatase.[24] Identifiers Symbol LMWPc Pfam PF01451 InterPro IPR017867 SMART SM00226 SCOP2 1phr / SCOPe / SUPFAM CDD cd00115 Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary PDB 1bvh​, 1c0e​, 1d1p​, 1d1q​, 1d2a​, 1dg9​, 1jf8​, 1jfv​, 1jl3​, 1ljl​

Protein-tyrosine phosphatase Structure of Yersinia protein tyrosine phosphatase.[25] Identifiers Symbol Y_phosphatase Pfam PF00102 Pfam clan CL0031 InterPro IPR000242 SMART SM00194 PROSITE PS50055 SCOP2 1ypt / SCOPe / SUPFAM CDD cd00047 Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary PDB 1a5y​, 1aax​, 1bzc​, 1bzh​, 1bzj​, 1c83​, 1c84​, 1c85​, 1c86​, 1c87​

Dual-specificity phosphatase, catalytic domain Structure of the dual-specificity protein phosphatase VHR.[26] Identifiers Symbol DSPc Pfam PF00782 Pfam clan CL0031 InterPro IPR000340 PROSITE PDOC00323 SCOP2 1vhr / SCOPe / SUPFAM CDD cd14498 Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary PDB 1d5r​, 1i9s​, 1i9t​, 1j4x​, 1m3g​, 1mkp​, 1ohc​, 1ohd​, 1ohe​, 2c46​

Protein-tyrosine phosphatase, SIW14-like Structure of a putative phosphoprotein phosphatase from Arabidopsis thaliana.[27] Identifiers Symbol Y_phosphatase2 Pfam PF03162 Pfam clan CL0031 InterPro IPR004861 CDD cd14528 Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary PDB 1xri​, 2q47​

Protein-tyrosine phosphatase-like, PTPLA Identifiers Symbol PTPLA Pfam PF04387 InterPro IPR007482 Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Individual PTPs may be expressed by all cell types, or their expression may be strictly tissue-specific. Most cells express 30% to 60% of all the PTPs, however hematopoietic and neuronal cells express a higher number of PTPs in comparison to other cell types. T cells and B cells of hematopoietic origin express around 60 to 70 different PTPs. The expression of several PTPS is restricted to hematopoietic cells, for example, LYP, SHP1, CD45, and HePTP.^[28] The expression of PTPN5 is restricted to the brain, and differs between brain regions, with no expression in the cerebellum.^[29][30][31]

• This article incorporates text from the public domain Pfam and InterPro: IPR000106

• PTP Summary and Relevant Publications at Monash University
• Protein-Tyrosine-Phosphatase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• EC 3.1.3.48