PROSITE documentation PDOC00323

Tyrosine specific protein phosphatases active site signature and domains profiles

Tyrosine specific protein phosphatases (EC 3.1.3.48) (PTPase) [1,2,3,4,5] are enzymes that catalyze the removal of a phosphate group attached to a tyrosine residue. These enzymes are very important in the control of cell growth, proliferation, differentiation and transformation. Multiple forms of PTPase have been characterized and can be classified into two categories: soluble PTPases and transmembrane receptor proteins that contain PTPase domain(s). The currently known PTPases are listed below:

Soluble PTPases.

• PTPN1 (PTP-1B).
• PTPN2 (T-cell PTPase; TC-PTP).
• PTPN3 (H1) and PTPN4 (MEG), enzymes that contain an N-terminal FERM domain (see <PDOC00566>) and could act at junctions between the membrane and cytoskeleton.
• PTPN5 (STEP).
• PTPN6 (PTP-1C; HCP; SHP) and PTPN11 (PTP-2C; SH-PTP3; Syp), enzymes which contain two copies of the SH2 domain at its N-terminal extremity. The Drosophila protein corkscrew (gene csw) also belongs to this subgroup.
• PTPN7 (LC-PTP; Hematopoietic protein-tyrosine phosphatase; HePTP).
• PTPN8 (70Z-PEP).
• PTPN9 (MEG2).
• PTPN12 (PTP-G1; PTP-P19).
• Yeast PTP1.
• Yeast PTP2 which may be involved in the ubiquitin-mediated protein degradation pathway.
• Fission yeast pyp1 and pyp2 which play a role in inhibiting the onset of mitosis.
• Fission yeast pyp3 which contributes to the dephosphorylation of cdc2.
• Yeast CDC14 which may be involved in chromosome segregation.
• Yersinia virulence plasmid PTPAses (gene yopH).
• Autographa californica nuclear polyhedrosis virus 19 Kd PTPase.

Dual specificity PTPases.

• DUSP1 (PTPN10; MAP kinase phosphatase-1; MKP-1); which dephosphorylates MAP kinase on both Thr-183 and Tyr-185.
• DUSP2 (PAC-1), a nuclear enzyme that dephosphorylates MAP kinases ERK1 and ERK2 on both Thr and Tyr residues.
• DUSP3 (VHR).
• DUSP4 (HVH2).
• DUSP5 (HVH3).
• DUSP6 (Pyst1; MKP-3).
• DUSP7 (Pyst2; MKP-X).
• Yeast MSG5, a PTPase that dephosphorylates MAP kinase FUS3.
• Yeast YVH1.
• Vaccinia virus H1 PTPase; a dual specificity phosphatase.

Receptor 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 but seems to affect substrate specificity of the first. In these domains, the catalytic cysteine is generally conserved but some other, presumably important, residues are not.

In the following table, the domain structure of known receptor PTPases is shown:

                                         Extracellular         Intracellular
                                         -------------------   -------------
                                         Ig  FN-3   CAH  MAM   PTPase

 Leukocyte common antigen (LCA) (CD45)    0     2     0    0      2
 Leukocyte antigen related (LAR)          3     8     0    0      2
 Drosophila DLAR                          3     9     0    0      2
 Drosophila DPTP                          2     2     0    0      2
 PTP-alpha (LRP)                          0     0     0    0      2
 PTP-beta                                 0    16     0    0      1
 PTP-gamma                                0     1     1    0      2
 PTP-delta                                0    >7     0    0      2
 PTP-epsilon                              0     0     0    0      2
 PTP-kappa                                1     4     0    1      2
 PTP-mu                                   1     4     0    1      2
 PTP-zeta                                 0     1     1    0      2

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.

We derived a signature pattern for PTPase domains centered on the active site cysteine.

There are three profiles for PTPases, the first one spans a short region that is common to both dual-specificity protein phosphatases and PTPases. The second and third ones cover the whole domain and are respectively specific for Ser/Thr and Tyr protein phosphatases and Tyr protein phosphatases.