PTPs as Drug Targets
In the early days of PTP research, these enzymes were mainly considered as housekeeping enzymes that turned signaling processes off. A more complicated picture later emerged showing PTPs both to be negative and positive regulators of signaling pathways. Despite this, most drug discovery activities in the PTP field have so far been directed towards development of inhibitors of PTPs that negatively regulate signaling pathways, thereby intensifying and/or prolonging signaling.
In particular, the insulin signaling pathway has received much attention based on the assumption that the insulin-resistant state in type 2 diabetes could be overcome by inhibiting PTPs that negatively regulate this pathway. Based on theoretical considerations, our own efforts began back in the early 1990s by re-cloning and expression of PTP1B as a tool (Hoppe et al. 1994), searching for novel PTPs (M0ller et al. 1994a,b), and by studying the tissue distribution of PTPs (Norris et al. 1997). We decided to focus on PTPs that negatively regulate upstream elements in the insulin-signaling pathway, preferentially the insulin receptor tyrosine kinase itself (M0ller et al. 1995). We assumed that even the unstimulated IR had to be controlled by counteracting PTPs, i.e., potentially selective inhibitors could be used not only to treat patients with type 2 diabetes, but also type 1 diabetes. Numerous studies have since then been devoted to identification of the insulin receptor-regulating PTPs (IR-PTP) and the development of selective inhibitors thereof (reviewed in Kennedy 1999; M0ller et al. 2000; Ramachandran and Kennedy 2003; Zhang and Lee 2003), namely: (1) brute force substrate trapping studies (Walchli et al. 2000); (2) in vitro studies with anti-sense oligonucleotides (Kulas et al. 1995); (3) tissue distribution analyses (Norris et al. 1997); (4) studies of the dynamics in subcellular distribution of PTPs (Calera et al. 2000); (5) insulin-based selection system analyses (M0ller et al. 1995); (6) overexpression studies. As a result, several candidate PTPs have been named, including PTP1B, PTPa (M0ller et al. 1995; Cong et al. 1999), and PTP-LAR (Ahmad et al. 1995; Kulas et al. 1995). As described above, PTP1B is clearly the PTP target that has been validated and addressed most in the diabetes and obesity field.
As recently pointed out by one of the key founders of the PTP field, it is important to remember that there is more to the PTP family than just PTP1B (Tonks 2003), and it should be remembered that other PTPs, in addition to PTP1B, may be involved in the negative regulation of insulin signaling. Also, other PTPs could potentially be attractive drug targets, such as CD45 in autoimmunity (Hermiston et al. 2003; Irie-Sasaki et al. 2003; Lee and Burke 2003) and SHP-1 in cancer (Wu et al. 2003). Further, other PTPs seem to be negative regulators of the immune system, by recruitment to receptor molecules with ITIMs (immunoreceptor tyrosine inhibitory motifs). It might therefore be speculated that inhibitors of such PTPs (e.g., SHP-1) enhance the activity of cells like natural killer cells (Jackson 2003). Additionally, LAR (Mooney and LeVea 2003) and PTPa (Pallen 2003) have been proposed as potential drug targets, and SHP-2 mutants are critically involved in the development of Noonan syndrome and juvenile myelomonocytic leukemia (Tartaglia et al. 2003).
In addition, PTP inhibitors may be useful for treatment of infectious diseases (reviewed in van Huijsduijnen et al. 2002). Thus, it has been found that Helicobacter pylori, a class I carcinogen, produces a protein, CagA, that activates SHP-2 leading to a growth factor-like response in gastric epithelial cells (Higashi et al. 2002; Hatakeyama 2003). Also, PTPZ and PTPa appear to be receptors for the H. pylori cytotoxin, VacA, that induces vacuolation, mi-tochondrial damage, cytochrome c release, and apoptosis of gastric epithelial cells (Yahiro et al. 1999; Yahiro et al. 2003). A number of bacterial pathogens have evolved strategies to destabilize signal transduction for their own benefit, and highly active PTPs seem to be used as such sophisticated viru lence factors (Clemens et al. 1991). As an example, the Yersinia PTP, which has served as an excellent research tool in a number of publications, has been shown to be essential for virulence (Guan and Dixon 1990). Similarly, a PTP in Salmonella seems to be required for full display of virulence (Kaniga et al. 1996; Murli et al. 2001). Ullrich and coworkers recently cloned and characterized two secretory PTPs from Mycobacterium, one of which was proposed as a candidate virulence gene (Koul et al. 2000).
It remains to be shown if some or all of the above-mentioned PTPs will eventually prove to be good drug target candidates. Clearly, additional basic science and preclinical work will be required to validate these candidates. In any case, selective, cellularly active PTP inhibitors would be invaluable tools in such assessments.
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