InterPro domain: IPR000242

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase; 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 and transformation [ 1 , 2 ]. The PTP superfamily can be divided into four subfamilies [ 3 ]:

• (1) pTyr-specific phosphatases
• (2) dual specificity phosphatases (dTyr and dSer/dThr)
• (3) Cdc25 phosphatases (dTyr and/or dThr)
• (4) LMW (low molecular weight) phosphatases

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

• Receptor-like, which are transmembrane receptors that contain PTPase domains [ 4 ]
• Non-receptor (intracellular) PTPases [ 5 ]

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share 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 [ 6 ]. Functional diversity between PTPases is endowed by regulatory domains and subunits.

This entry represents the PTPase domain found in several tyrosine-specific protein phosphatases (PTPases).

Structurally, 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. The cytoplasmic region generally contains two copies of the PTPase domain. The first seems to have enzymatic activity, while the second is inactive. The inactive domains of tandem phosphatases can be divided into two classes. Those which bind phosphorylated tyrosine residues may recruit multi-phosphorylated substrates for the adjacent active domains and are more conserved, while the other class have accumulated several variable amino acid substitutions and have a complete loss of tyrosine binding capability. The second class shows a release of evolutionary constraint for the sites around the catalytic centre, which emphasises a difference in function from the first group. There is a region of higher conservation common to both classes, suggesting a new regulatory centre [ 7 ]. PTPase domains consist of about 300 amino acids. There are two conserved cysteines, the second one has been shown to be absolutely required for activity. Furthermore, a number of conserved residues in its immediate vicinity have also been shown to be important.

1. Protein tyrosine phosphatases: mechanisms of catalysis and regulation. Cell. Mol. Life Sci. 2, 633-41
2. Receptor and nonreceptor protein tyrosine phosphatases in the nervous system. Protein Sci. 60, 2465-82
3. An overview of the protein tyrosine phosphatase superfamily. Dev. Biol. 3, 739-48
4. The crystal structure of human receptor protein tyrosine phosphatase kappa phosphatase domain 1. null 15, 1500-5
5. The nonreceptor protein tyrosine phosphatase corkscrew functions in multiple receptor tyrosine kinase pathways in Drosophila. null 180, 63-81
6. The structure and mechanism of protein phosphatases: insights into catalysis and regulation. null 27, 133-64
7. Evolution of the multifunctional protein tyrosine phosphatase family. Mol. Biol. Evol. 21, 625-31