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Review
, 402 (1), 1-15

Protein Tyrosine Phosphatase Function: The Substrate Perspective

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Review

Protein Tyrosine Phosphatase Function: The Substrate Perspective

Tony Tiganis et al. Biochem J.

Abstract

It is now well established that the members of the PTP (protein tyrosine phosphatase) superfamily play critical roles in fundamental biological processes. Although there has been much progress in defining the function of PTPs, the task of identifying substrates for these enzymes still presents a challenge. Many PTPs have yet to have their physiological substrates identified. The focus of this review will be on the current state of knowledge of PTP substrates and the approaches used to identify them. We propose experimental criteria that should be satisfied in order to rigorously assign PTP substrates as bona fide. Finally, the progress that has been made in defining the biological roles of PTPs through the identification of their substrates will be discussed.

Figures

Figure 1
Figure 1. Structure of classical PTPs
Schematic representation of the classical PTPs grouped as either receptor-like PTPs or non-transmembrane PTPs which contain various functional domains [BRO-1, BRO-1 homology; CAH, carbonic anhydrase-like; Cad, cadherin-like juxtamembrane sequence; FERM, FERM (4.1/ezrin/radixin/moesin) domain; FN, fibronectin type III-like domain; Gly, glycosylated; HD, histidine domain; Ig, immunoglobulin domain; KIM, kinase-interacting 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]. Some of the receptor-like PTPs contain a membrane proximal PTP domain that is catalytically active and a membrane-distal PTP domain (PTP pseudo-phosphatase domain) that has residual activity. The non-transmembrane PTPs all contain a single PTP domain.
Figure 2
Figure 2. Characterization of PTP substrates
The three proposed criteria for the assignment of a tyrosine-phosphorylated protein as a PTP substrate. To define a tyrosine-phosphorylated protein as a PTP substrate, one should (i) demonstrate interaction of the substrate with the PTP substrate-trapping mutant, (ii) modulate the substrate tyrosine-phosphorylation level in a cellular context, and (iii) dephosphorylate the substrate in vitro. A combination of overexpression of the wild-type PTP and substrate-trapping PTP mutant along with underexpression approaches (e.g. RNAi, antisense and knockout cells) can be employed in order to test whether a putative PTP substrate satisfies these criteria (see the text for details).
Figure 3
Figure 3. SHP-2 signals positively by inactivating negative regulators of small GTPases and SFKs
SHP-2 dephosphorylates the EGFR (Tyr992) and Gab1 (Grb2-associated binder-1) to prevent the translocation of p120 RasGAP to the EGFR or Gab1 where p120 RasGAP inactivates Ras (broken lines). By interfering with p120 RasGAP localization SHP-2 facilitates the activation of Ras in response to EGF (epidermal growth factor). When phosphorylated, p190B RhoGAP co-localizes with RhoA in lipid rafts to inhibit RhoA activation (broken lines). Dephosphorylation of p190B RhoGAP displaces it from lipid rafts where it is no longer able to inactivate RhoA. In muscle cells, SHP-2 dephosphorylates p190B RhoGAP, thereby promoting RhoA-mediated muscle differentiation. SHP-2 controls localization of the negative regulator of the SFKs, CSK. CSK binds phosphorylated PAG/Cbp and paxillin where it is able to inactivate the SFKs (broken lines). SHP-2 dephosphorylates PAG/Cbp and paxillin causing CSK to dissociate from these complexes preventing it from inhibiting the SFKs. SHP-2 thus promotes SFK activation in the control of cell proliferation, cell survival and cytoskeletal organization.
Figure 4
Figure 4. Physiological roles of PTP1B substrates
A number of receptor tyrosine kinases are dephosphorylated by PTP1B, including EGFR, PDGFR, CSF-1 receptor (CSF-1R) and IGF-1 receptor (IGF-1R). Dephosphorylation of these receptors by PTP1B antagonizes receptor functions such as cell proliferation and survival. c-Src and p130Cas serve as PTP1B substrates in the control of cytoskeletal organization. In the case of c-Src, dephosphorylation at Tyr527 by PTP1B activates c-Src. PTP1B dephosphorylates the IR (Tyr1162/Tyr1163) and JAK2 (Tyr1007/Tyr1008). Right-hand panel: IR and JAK2 are involved in metabolic homoeostasis and PTP1B functions in the brain to dephosphorylate JAK2 to limit leptin signalling in the control of food intake and energy expenditure. In peripheral tissues, PTP1B dephosphorylates the IR to inhibit glucose uptake in skeletal muscle and liver.
Figure 5
Figure 5. Conforming to the criteria of substrate identification
Substrates of PEP, PTP-PEST and PTP-MEG2 are shown. Proliferation of effector/memory T-cells is negatively regulated by PEP, which dephosphorylates and inactivates Lck and ZAP-70. PTP-PEST regulates cytoskeletal organization by dephosphorylating p130Cas, p190A RhoGAP and Vav2. PTP-MEG2 dephosphorylates NSF (Tyr83) to regulate secretory vesicle fusion.

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