Protein tyrosine phosphatase

Protein-tyrosine-phosphatase
Identifiers
EC number	3.1.3.48
CAS number	Template:CAS
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 are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. 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 strengthening.

Functions

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

Classification

By mechanism

The PTP superfamily can be divided into four subfamilies.

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

Class I

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 phosphatase
  • 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, Fragile X Syndrome schizophrenia, and Parkinson’s disease. Decreased levels of PTPN5 has been implicated in Huntington's disease, cerebral ischemia alcohol abuse, and stress disorders. Together these findings indicate that only at optimal levels of PTPN5 is synaptic function unimpaired.

Class II

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

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

Class III

Cdc25 phosphatases (dTyr and/or dThr)

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

Class IV

pTyr-specific phosphatases

The class IV PTPs contains four members, Eya1-4.

This class is believed to have evolved separately from the other three.

By location

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

• Receptor-like, which are transmembrane receptors that contain PTPase domains. 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

Common elements

All PTPases 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. 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. Identifiers Symbol LMWPc Pfam PF01451 InterPro IPR017867 SMART SM00226 SCOP 1phr SUPERFAMILY 1phr Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Protein-tyrosine phosphatase Structure of Yersinia protein tyrosine phosphatase. Identifiers Symbol Y_phosphatase Pfam PF00102 Pfam clan CL0031 InterPro IPR000242 SMART SM00194 PROSITE PS50055 SCOP 1ypt SUPERFAMILY 1ypt Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Dual-specificity phosphatase, catalytic domain Structure of the dual-specificity protein phosphatase VHR. Identifiers Symbol DSPc Pfam PF00782 Pfam clan CL0031 InterPro IPR000340 PROSITE PDOC00323 SCOP 1vhr SUPERFAMILY 1vhr Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Protein-tyrosine phosphatase, SIW14-like Structure of a putative phosphoprotein phosphatase from Arabidopsis thaliana. Identifiers Symbol Y_phosphatase2 Pfam PF03162 Pfam clan CL0031 InterPro IPR004861 Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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

Expression pattern

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. The expression of PTPN5 is restricted to the brain. Differential expression of PTPN5 is found in many brain regions, with no expression in the cerebellum.

Sources

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

External links

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