Protein tyrosine phosphatases as potential therapeutic targets
Abstract
Rong-jun HE#, Zhi-hong YU#, Ruo-yu ZHANG, Zhong-yin ZHANG*
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA
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.
Keywords: drug target; protein tyrosine phosphatases; PTP1B; Src homology phosphotyrosyl phosphatase 2; lymphoid-specific tyrosine phosphatase; Fas associated phosphatase-1; CD45 antigen; striatal enriched tyrosine phosphatases; mitogen-activated protein kinase phosphatases; phosphatases of regenerating liver-1; low molecular weight PTPs; CDC25
This work was supported in part by National Institutes of Health Grants CA69202 and CA126937.
# The first two authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail zyzhang@iu.edu
Received 2014-05-29 Accepted 2014-07-31
Keywords:
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA
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.
Keywords: drug target; protein tyrosine phosphatases; PTP1B; Src homology phosphotyrosyl phosphatase 2; lymphoid-specific tyrosine phosphatase; Fas associated phosphatase-1; CD45 antigen; striatal enriched tyrosine phosphatases; mitogen-activated protein kinase phosphatases; phosphatases of regenerating liver-1; low molecular weight PTPs; CDC25
This work was supported in part by National Institutes of Health Grants CA69202 and CA126937.
# The first two authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail zyzhang@iu.edu
Received 2014-05-29 Accepted 2014-07-31