Protein tyrosine phosphatases as potential therapeutic targets

Abstract

Protein tyrosine phosphorylation is a key regulatory process in virtually all aspects of cellular functions. Dysregulation of protein tyrosine phosphorylation is a major cause of human diseases, such as cancers, diabetes, autoimmune disorders, and neurological diseases. Indeed, protein tyrosine phosphorylation-mediated signaling events offer ample therapeutic targets, and drug discovery efforts to date have brought over two dozen kinase inhibitors to the clinic. Accordingly, protein tyrosine phosphatases (PTPs) are considered next-generation drug targets. For instance, PTP1B is a well-known targets of type 2 diabetes and obesity, and recent studies indicate that it is also a promising target for breast cancer. SHP2 is a bona-fide oncoprotein, mutations of which cause juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors. In addition, LYP is strongly associated with type 1 diabetes and many other autoimmune diseases. This review summarizes recent findings on several highly recognized PTP family drug targets, including PTP1B, Src homology phosphotyrosyl phosphatase 2(SHP2), lymphoid-specific tyrosine phosphatase (LYP), CD45, Fas associated phosphatase-1 (FAP-1), striatal enriched tyrosine phosphatases (STEP), mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1), phosphatases of regenerating liver-1 (PRL), low molecular weight PTPs (LMWPTP), and CDC25. Given that there are over 100 family members, we hope this review will serve as a road map for innovative drug discovery targeting PTPs.

Figure 1

Human PTP classification. The gene encoding individual PTPs is shown in parenthesis after the PTP name. PTPs discussed in this review are highlighted in italic and bold font.

Figure 2

The schematic PTP structure discussed in this review.

Figure 3

The physiological/pathological signal pathways involving PTP1B (A), SHP2 (B), LYP and CD45 (C), FAP-1 (D), and STEP (E). Arrow represents positive regulation. T-bar represents dephosphorylation if it points to a phosphate group or specific pY, otherwise it represents negative regulation. Dashed lines in panel (D) represent binding interaction. See the text for regulation details.

Figure 4

The structure of PTP1B (A), SHP2 (B), and LYP (C) inhibitors mentioned in this review.

Figure 5

The physiological/pathological signal pathways involving MKP-1 (A) and PRL1/2/3 (B). Arrow represents positive regulation. T-bar represents dephosphorylation if it points to a phosphate group or specific pY, otherwise it represents negative regulation. See the text for regulation details.

Figure 6

The physiological/pathological signal pathways involving LMWPTP (A) and CDC25 (B). Arrow represents positive regulation. T-bar represents dephosphorylation if it points to a phosphate group or specific pY, otherwise it represents negative regulation. See the text for regulation details.