2002;84:840C6. activities. For example, phosphorylation of human c-Src at Tyr-530 by Csk tyrosine kinase inhibits the c-Src tyrosine kinase activity. Dual phosphorylation of Cdk1 at Thr-14 and Tyr-15 blocks its kinase activity. Dephosphorylation of these residues leads to enzyme activation. In fact, increasing evidence suggests that cell signaling requires coordinate action of both PTK and PTP activities [5]. Therefore, PTPs could cooperate with PTKs, in addition to antagonizing them, in promoting cancer growth and progression. Open in a separate window Fig. (1) Positive and negative roles of tyrosine phosphorylation in cell signaling. In this illustration, three tyrosine residues (Y1, Y2, Y3) on a protein may be subject to phosphorylation by a PTK. Phosphorylation of Y1 increases the activity of the protein. Phosphorylation of Y2 inhibits the activity of the protein. Phosphorylation of Y3 induces feedback inhibition such as recruitment of E3 ligase that causes degradation of the protein or GTPase Activator Protein (GAP) that turns off G-proteins. While dephosphorylation of Y1 by PTP1 inactivate the protein, dephosphorylation of Y2 and Y3 by PTP2 and PTP3 are necessary for sustained activity of the protein. Thus, PTP1 is a negative regulator whereas PTP2 and PTP3 are positive regulators that coordinately control the activity of the protein. Another dogma contributing to the slow start Alarelin Acetate of PTP drug discovery efforts was that PTKs are highly regulated and specific, whereas a few constitutive, non-specific PTPs passively counteract the function of PTKs [14]. It is now known that there are at least 107 PTP genes in the human genome, providing highly regulated and specific function in various types of human cells [10, 13]. Human PTPs are grouped into three classes of Cys-based PTPs and a fourth family of Asp-based PTPs. Although designated as PTPs, besides phosphotyrosine-specific phosphatases, PTPs include dual specificity phosphatases (DSPs) that dephosphorylate protein tyrosine and serine/threonine residues and phosphatases that their known physiological substrates are phosphothreonine residues, phospholipids, and mRNA. Among Class I phosphotyrosine-specific classical PTPs, the transmembrane PTP (encoded by the Alarelin Acetate gene) is an activator of c-Src. The non-receptor PTP Shp2 ((DEP1 gene)-null mice do not develop spontaneous tumor [33]. Therefore, although pre-clinical and clinical evaluations will be required, it is predicted that a selective PTP inhibitor, even if it weakly cross-inhibits a putative PTP tumor suppressor, is unlikely to cause therapy-induced tumor and therefore it is acceptable as an anticancer drug candidate in this regard. Another issue is the potential toxicity of inhibiting RAB11B the targeted PTPs in normal cells. Although this needs to be tested in each case through clinical trials, it is believed that therapeutic windows exist for exploration of selective toxicity to cancer cells. PTPs selected as drug targets usually are aberrantly active in the cancer cells, which may confer specific dependency of cancer cells to the PTPs. For instance, it has been reported that Shp2 knockdown specifically inhibits primary chronic myeloid leukemia (CML) cells but not normal CD34+ cells [34]. Furthermore, for certain terminal diseases, short term, low Alarelin Acetate grade toxicity with drugs that have proven benefits to the disease management may be acceptable. In the following sections, we describe Shp2 as a target for novel anticancer drug discovery Alarelin Acetate and summarize other established and potential PTP targets for anticancer drug discovery. SHP2 (corkscrew (csw) gene product. Shortly after mammalian Shp2 was cloned, several laboratories tested effects of catalytic-Cys mutated Shp2 on insulin- or epidermal growth factor (EGF)-stimulated Ras and Erk1/Erk2 (Erk1/2) activation. These experiments consistently showed that a catalytic-inactive Shp2 displayed a dominant-negative effect on insulin- or EGF-induced Ras/Erk1/2 activation [36, 37]..
