Physiological Signaling Specificity by Protein Tyrosine Phosphatases

Abstract

Intracellular signaling pathways that are mediated by tyrosyl phosphorylation are controlled through the balanced and opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). The view that PTPs are equal contributing partners in the regulation of cellular tyrosyl phosphorylation continues to mature. However, there still remains the perception that PTPs play largely housekeeping roles. A growing body of evidence firmly dispels this perception, and it is evident that PTPs function with stringent signaling specificity, in concert with their PTK counterparts, to define specific biological outcomes. In this review, we will focus on illustrating that PTPs exhibit defined substrate specificity and subsequently regulate signaling pathways in a precise manner. The PTP SuperfamilyThe superfamily of PTPs is characterized by a consensus signature motif represented by HC(X) 5 R, which defines the active site of these enzymes. Two classes of PTPs can be defined (FIGURE 1). The first class is composed of classical PTPs that are defined by cysteine-based phosphotyrosine specificity, and the second class constitutes the dual-specificity phosphatases (DSPs). There are 37 classical human PTP genes that contain at least one PTP domain of ~280 amino acids. The DSPs are much larger in number, and there are 65 of these genes in the human genome. The classical PTP genes can be further subdivided into transmembrane receptor PTPs (RPTPs), or non-transmembrane PTPs, which localize to the cytoplasm (2, 4, 68). There are 12 RPTPs containing tandem PTP domains with the remainder containing a single PTP domain. The membrane-proximal PTP domain (D1) and membrane-distal PTP domain (D2) serve distinct roles. In the majority of cases, the D1 PTP domain comprises the active domain, whereas in most cases, but not all, the D2 domain serves a negative regulatory role. Although still quite controversial, evidence has been put forth to suggest that RPTPs are regulated through dimerization whereby RPTP activity is inhibited upon dimerization. However, there is also evidence against such a model of RPTP regulation, and further work in this particular area is warranted. Much like the RTKs, RPTPs utilize their diverse extracellular domains to transduce intracellular signals through binding to soluble ligands, but, in addition, RPTPs utilize their extracellular domains to mediate cell-cell and cell-matrix interactions (33,35,45,73). The nontransmembrane or cytoplasmic PTPs contain a single PTP domain, and their diversity is derived through noncatalytic regulatory domains that reside either at the NH 2 or COOH terminus of the PTP domain (2-3, 68). The noncatalytic domains are critical for exerting PTP substrate specificity and include one or more of the following features: 1) regulation of PTP activity, 2) directing subcellular localization, and 3) targeting PTP protein-protein interactions. Hence, the noncatalytic regions of the non-transmembrane PTPs offer a broad level of structural diversity, and together with the PTP...

Mitogen-Activated Protein Kinases and Mitogen-Activated Protein Kinase Phosphatases in Regenerative Myogenesis and Muscular Dystrophy

“…The MKPs belong to a sub-class of protein tyrosine phosphatases known as the dual-specificity protein phosphatases (DUSP) (Boutros et al, 2008;Soulsby and Bennett, 2009;Tonks, 2006). The DUSPs are characterized by a consensus signature motif represented by HC(X) 5 R which defines the active site of these enzymes (Soulsby and Bennett, 2009;Tonks, 2006).…”

Receptor Protein Tyrosine Phosphatase-Receptor Tyrosine Kinase Substrate Screen Identifies EphA2 as a Target for LAR in Cell Migration

“…ver the last decade, the field of protein tyrosine phosphatases (PTPs) has matured to a level where it is now fully appreciated that these enzymes play critical roles in the regulation of numerous physiological processes (1,2). Moreover, recent advances point to the PTP family of enzymes as targets for the cause of several human diseases (1)(2)(3)(4)(5)(6)(7)(8).…”

“…Moreover, recent advances point to the PTP family of enzymes as targets for the cause of several human diseases (1)(2)(3)(4)(5)(6)(7)(8). Therefore, understanding the mechanisms of PTP signaling will yield important insight into the molecular pathogenesis of human disease.…”

“…The PTP superfamily consists of 107 PTPs in the human genome (1,2,9). The classical PTPs dephosphorylate tyrosyl-phosphorylated proteins and are divided into receptor-like PTPs (RPTPs) and nonreceptor PTPs (2,10).…”

MAPK Pathway in Skeletal Muscle Diseases

“…One mechanism involves the dephosphorylation and thus inactivation of MAPKs by the MAPK phosphatases (MKPs) [5]. MKPs, also known as dual-specificity protein phosphatases (DUSPs), are a group of 10 catalytically active protein tyrosine phosphatases [9,20,21]. MKPs inactivate MAPKs through dephosphorylation of MAPKs on regulatory threonine and tyrosine residues.…”