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Review 2.1

PTP Family

Members of the PTP superfamily of structurally related enzymes are defined by a highly conserved catalytic domain. Within this 250 amino acid region, the active site signature sequence [HCXXGXXR] contains the invariant cysteine residue that is critical for PTP activity (Tonks and Neel 2001). Sequence data from the human genome and recent estimates from the literature predict the existence of 117 members for the PTP family (see the Gene Ontology Consortium at http://www.geneontology.org/ and http:// science.novonordisk.com/ptp/). Based on their sequences, structures, and functions we divided the PTP family into three categories: (1) the low molecular weight PTPs (LMW PTPs), (2) the dual-specific phosphatase (DSP), and (3) the phosphotyrosine-specific enzymes (classical PTPs).

LMW PTPs represent a small group of 18-kDa enzymes with broad tissue expression (Raugei et al. 2002). Overexpression of LMW PTPs in cells has been shown to dephosphorylate the platelet-derived growth factor receptor (PDGFR) (Chiarugi et al. 1995), p190RhoGTPase-activating protein (p190RhoGAP) (Chiarugi et al. 2000), as well as the epinephrineA2 (EphA2) kinase (Kikawa et al. 2002). These studies link LMW PTPs to both growth factor and adhesion signaling, suggesting that they may be important for many cellular processes, including mitogenesis and transformation. Recently, LMW PTP was also proposed to play a positive role in T cell receptor signal ing similar to the one proposed for CD45 (Bottini et al. 2002). However, the physiological functions of these enzymes remain unclear.

DSPs have the ability to dephosphorylate both tyrosine and serine/threo-nine residues. The most prominent members include the Vaccinia virus phosphatase-related enzymes, cell division cycle 25 (CDC25), and the mito-gen-activated protein kinase (MAPK) phosphatases (MKPs). The best-characterized functions of these examples involve the regulation of the MAPK pathway and cell cycle progression (Keyse 2000; Lyon et al. 2002). Another interesting group of DSPs include the PTEN (phosphatase and tensin homolog deleted on chromosome 10) and myotubularin phosphatases (Maehama et al. 2001). Although the sequence of their catalytic domains is similar to other DSPs, both PTEN and myotubularin act primarily as phos-phoinositide phosphatases. In contrast, their activity on protein substrates remains in doubt. Nevertheless, the importance of these two enzymes is highlighted by the presence of mutations that are responsible for severe human diseases, including cancer and muscular development.

The classical PTPs—the major group of the PTP family—comprise two groups, the intracellular and transmembrane (receptor type) enzymes, from which 17 subtypes were derived based upon their sequence similarity among catalytic PTP domains (Andersen et al. 2001). The receptor type PTPs generally contain an extra-cellular segment with putative ligand-binding domains, a single transmembrane region and one or two cytoplasmic catalytic domains, where the first domain contains most if not all catalytic activity. The intracellular PTPs have a single catalytic domain and varying amino- or car-boxy-terminal extensions containing protein-binding domains that are believed to have targeting or regulatory functions (Tonks and Neel 2001).

Despite the large heterogeneity in all the PTP subgroups, the crystal structure of several members (mostly catalytic domains) revealed that they all display a similar core folding feature (Barford 1999; Andersen et al. 2001). Thus, this common active site structure suggests that these enzymes use a similar mechanism for catalysis (Zhang 1998; Li and Dixon 2000; Kol-modin and Aqvist 2001).

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