Physiological signaling specificity by protein tyrosine phosphatases

Abstract

Protein tyrosine phosphatases (PTPs) are now recognized to be involved in a multitude of signaling events that control fundamental biological processes such as cell growth, differentiation, apoptosis, and cell movement. PTPs, which were initially thought to be less discriminating in their actions compared with their protein tyrosine kinase counterparts, are now known to regulate these various biological processes in a precise manner. This review will focus on the concept that PTPs exhibit remarkable signaling specificity through intrinsic differences between their PTP domains and through various modes of regulation that endows them with the capacity to promote unique physiological responses.

FIGURE 1.. The superfamily of protein tyrosine phosphatases and dual-specificity phosphatases

A: the superfamily of protein tyrosine phosphatases. The protein tyrosine phosphatase superfamily of enzymes is represented schematically, depicting receptor-like and non-transmembrane PTPs. Note the diverse extracellular domains of the receptor-like PTPs and non-catalytic domains of the non-transmembrane PTPs. BRO-1, BRO-1 homology; CAH, carbonic anhydrase-like; Cad, cadherin-like juxtamembrane sequence; FERM, FERM domain; FN, fibronectin type III-like domain; Gly, glycosylated; HD, histidine domain; Ig, immunoglobulin domain; KIM, kinase-interaction motif; MAM, mephrin/A5/μ domain; Pro, proline-rich; RGDS, RGDS-adhesion recognition motif; SEC14, SEC14/cellular retinaldehyde-binding protein-like; SH2, Src-homology 2. B: the dual-specificity phosphatases (DSPs) are quite diverse. Shown here are those representing the MAP kinase phosphatases (MKPs). MKPs that are shown in gray shuttle between the nucleus and cytoplasm. MK-STYK is presumed to be catalytically inactive, containing a substitution for the essential cysteine residue.

FIGURE 2.. Factors that determine the specificity of PTP signaling

Several factors control a PTP’s ability to discriminate between multiple tyrosyl-phosphorylated targets, allowing the PTP to signal in a highly specific manner and thus generate defined physiological responses. These factors include the subcellular location of the PTP, posttranslational modifications, which regulate PTP activity, and intrinsic structural differences within the PTP domain itself. See text for details and examples.

FIGURE 3.. Closely related PTPs regulate vastly different physiological responses

Schematic highlighting the structural similarities and functional differences between closely related PTPs. Despite high overall homology, these enzymes generate unique physiological responses. This is due, in part, to variations in their expression pattern and subcellular localization. Intrinsic differences within the PTP domain and noncatalytic domains also contribute to their unique signaling abilities. The examples shown represent PTP-1B and TC-PTP (A) and SHP-1 and SHP-2 (B).

FIGURE 4.. MAP kinase phosphatases (MKPs) coordinate compartmentalized MAP kinase dephosphorylation

MKPs shown with solid arrows are those exhibiting stronger substrate preference to a particular MAPK than those shown with the lighter broken arrow. MKPs exert specific signaling through temporal, spatial, and MAPK-selective dephosphorylation that integrate to produce defined effector responses or gene expression events.