CD45

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; 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 and transformation []. The PTP superfamily can be divided into four subfamilies []:

• (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 []
• Non-receptor (intracellular) PTPases []

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 []. Functional diversity between PTPases is endowed by regulatory domains and subunits.

This entry repesents the PTP-signature motif that characterises the catalytic site, and which encompasses only part of the PTPase domain structure.

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; 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 and transformation []. The PTP superfamily can be divided into four subfamilies []:

• (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 []
• Non-receptor (intracellular) PTPases []

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 []. Functional diversity between PTPases is endowed by regulatory domains and subunits.

This entry repesents several receptor and non-receptor protein-tyrosine phosphatases.

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 []. 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.

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; 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 and transformation []. The PTP superfamily can be divided into four subfamilies []:

• (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 []
• Non-receptor (intracellular) PTPases []

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 []. Functional diversity between PTPases is endowed by regulatory domains and subunits.

This entry includes proteins of two subfamilies: Ser/Thr (EC: 3.1.3.16) and Tyr dual specificity protein phosphatase and tyrosine specific protein phosphatase (EC: 3.1.3.48). Both of these subfamilies may also have inactive phosphatase domains, and dependent on the domain composition this loss of catalytic activity has different effects on protein function. Inactive single domain phosphatases can still specifically bind substrates, and protect against dephosphorylation, while the inactive domains of tandem phosphatases can be further subdivided 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 regulatory centre [].

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 both the serine/threonine or tyrosine-bound phosphate group from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. Dual specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle. Tyrosine specific protein phosphatases catalyze the removal of a phosphate group attached to a tyrosine residue. They are also very important in the control of cell growth, proliferation, differentiation and transformation.

This entry spans a short region that is common to both dual-specificity protein phosphatases and protein-tyrosine phosphatase.

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; 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 and transformation []. The PTP superfamily can be divided into four subfamilies []:

• (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 []
• Non-receptor (intracellular) PTPases []

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 []. Functional diversity between PTPases is endowed by regulatory domains and subunits.

This entry represents 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 both the serine/threonine or tyrosine-bound phosphate group from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. Dual specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle. The crystal structure of a human DSP, vaccinia H1-related phosphatase (or VHR), has been determined at 2.1 angstrom resolution []. A shallow active site pocket in VHR allows for the hydrolysis of phosphorylated serine, threonine, or tyrosine protein residues, whereas the deeper active site of protein tyrosine phosphatases (PTPs) restricts substrate specificity to only phosphotyrosine. Positively charged crevices near the active site may explain the enzyme's preference for substrates with two phosphorylated residues. The VHR structure defines a conserved structural scaffold for both DSPs and PTPs. A "recognition region" connecting helix alpha1 to strand beta1, may determine differences in substrate specificity between VHR, the PTPs, and other DSPs.

These proteins may also have inactive phosphatase domains, and dependent on the domain composition this loss of catalytic activity has different effects on protein function. Inactive single domain phosphatases can still specifically bind substrates, and protect again dephosphorylation, while the inactive domains of tandem phosphatases can be further subdivided 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 [].

This entry includes proteins of two subfamilies: Ser/Thr (EC: 3.1.3.16) and Tyr dual specificity protein phosphatase and tyrosine specific protein phosphatase (EC: 3.1.3.48). Both of these subfamilies may also have inactive phosphatase domains, and dependent on the domain composition this loss of catalytic activity has different effects on protein function. Inactive single domain phosphatases can still specifically bind substrates, and protect against dephosphorylation, while the inactive domains of tandem phosphatases can be further subdivided 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 regulatory centre [].

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 both the serine/threonine or tyrosine-bound phosphate group from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. Dual specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle. Tyrosine specific protein phosphatases catalyze the removal of a phosphate group attached to a tyrosine residue. They are also very important in the control of cell growth, proliferation, differentiation and transformation.

Fibronectin is composed of three repeating structural motifs, of which one is the fibronectin III (FnIII) module. The three modules form a linear sequence of multiple tandem copies connected by short linker peptides. The secondary structure of the FnIII10 module, which is the only fibronectin module to possess an integrin binding RGD motif, consists of two beta-sheets containing the antiparallel beta-strands ABE and DCFG, respectively, which fold up to form a beta-sandwich. The RGD sequence is located in the loop connecting the beta-strands [].

Fibronectins are multi-domain glycoproteins found in a soluble form in plasma, and in an insoluble form in loose connective tissue and basement membranes []. They contain multiple copies of 3 repeat regions (types I, II and III), which bind to a variety of substances including heparin, collagen, DNA, actin, fibrin and fibronectin receptors on cell surfaces. The wide variety of these substances means that fibronectins are involved in a number of important functions: e.g., wound healing; cell adhesion; blood coagulation; cell differentiation and migration; maintenance of the cellular cytoskeleton; and tumour metastasis []. The role of fibronectin in cell differentiation is demonstrated by the marked reduction in the expression of its gene when neoplastic transformation occurs. Cell attachment has been found to be mediated by the binding of the tetrapeptide RGDS to integrins on the cell surface [], although related sequences can also display cell adhesion activity.

Plasma fibronectin occurs as a dimer of 2 different subunits, linked together by 2 disulphide bonds near the C terminus. The difference in the 2 chains occurs in the type III repeat region and is caused by alternative splicing of the mRNA from one gene []. The observation that, in a given protein, an individual repeat of one of the 3 types (e.g., the first FnIII repeat) shows much less similarity to its subsequent tandem repeats within that protein than to its equivalent repeat between fibronectins from other species, has suggested that the repeating structure of fibronectin arose at an early stage of evolution. It also seems to suggest that the structure is subject to high selective pressure [].

The fibronectin type III repeat region is an approximately 100 amino acid domain, different tandem repeats of which contain binding sites for DNA, heparin and the cell surface []. The superfamily of sequences believed to contain FnIII repeats represents 45 different families, the majority of which are involved in cell surface binding in some manner, or are receptor protein tyrosine kinases, or cytokine receptors.

This group represents a leukocyte common antigen.