2013;25(2):156C68. context of cancer, diabetes, hereditary disorders and other diseases. In particular, there have been several recent advances in our understanding of phosphatases involved in regulation of vascular endothelial growth factor receptor 2 (VEGFR2) signaling. The receptor is the principal signaling molecule mediating a wide spectrum of VEGF signal and, thus, is usually of paramount significance in a wide variety of diseases ranging from cancer to cardiovascular to ophthalmic. This review focuses on the current knowledge about protein phosphatases’ regulation of VEGFR2 signaling and how these enzymes can modulate affect its biological effects. whose Cys-residue is necessary for the phosphatase activity and is susceptible to inactivation by reactive oxygen species (ROS)-mediated oxidation. PTPRs contain an extracellular domain that may bind soluble ligands or interact with extracellular matrix components, while the catalytic domain is located in the intracellular part of the protein. Conversely, PTPNs are found in the cytosol or bound to intracellular membrane compartments and presents a variety of regulatory domains that are critical for correct spatial and temporal localization. PSPs mainly exist as holoenzymes consisting of a catalytic subunit and one or more regulatory subunits. PSP catalytic mechanisms are less conserved compared to PTPs and are usually classified into three SHH families: phosphoprotein phosphatases (PPPs), metal-dependent protein phosphatases (PPMs), and aspartate-based phosphatases. Although there is a limited number of PSP catalytic subunits (30) , a large number of regulatory subunits that can associate with the same catalytic subunit may provide substrate and localization specificity. The reader is referred to recent reviews on this subject for a more exhaustive description of phosphatases classification, mechanism of action and molecular structure, [2, 3, 7]. VEGFR2 is a Receptor Tyrosine Kinase (RTK) predominantly expressed in endothelial cells (ECs) and their embryonic precursors [8-10], although its expression can be detected in neuronal cells and hematopoietic stem Senkyunolide I cells . Deletion of VEGFR2  or its main ligand VEGFA [13, 14] leads to early embryonic lethality in mice (E8.5/9.5 and E9.5/10.5, respectively) due to severe impairment of vascular development and hematopoietic cell maturation. Furthermore, deletion of a single VEGFA allele is sufficient to induce embryonic death at E11-12 [13, 14]. VEGFA was initially named as the Vascular Permeability Factor (VPF) after its ability to induce Evans Blue extravascular leakage in guinea pig back skin , however, it is now evident that VEGFA plays a larger role in both embryonic development and adult life [16, 17]. The activation of VEGFR2 by VEGFA can initiate multiple Senkyunolide I signaling pathways that orchestrate a variety of complex biological Senkyunolide I effects, such as endothelial cells maturation, vessel lumen formation, vascular permeability, vasodilation, angiogenesis and arteriogenesis [18-21]. Furthermore, knock-in mice which express only selected VEGFA splicing isoforms show marked phenotype differences; this suggests some degree of function segregation between the isoforms [16, 19] Mounting evidence during the last decade demonstrates that phosphatases do not merely switch-off, but can finely modulate molecular and cellular responses by regulating phosphorylation events in negative or positive nodes of a signaling pathway . A number of recent reviews have addressed the role of protein phosphatases in animal disease models and human diseases such as cancer [23, 24], diabetes , antiplatelet therapy , and hereditary disorders . This review will focus on phosphatases known to affect VEGFR2 signaling (and its biological effects) by means of targeting phosphorylation of the receptor itself (Fig.1) or that of its downstream signal transducers (Fig. 2). VEGFR2 signaling plays an important role in diseases such as cancer , cardiovascular disease , Senkyunolide I retinopathies (age-related macular degeneration, AMD; diabetic macular edema, DME; retinopathy of prematurity, ROP; and others) , cerebrovascular disorders  and stroke , therefore phosphatases that modulate its signaling (Tables 1-?-2)2) may represent novel pharmacological targets to improve therapy of these diseases. Open in a separate window Fig. 1 Summary of PTPs that dephosphorylate VEGFR2Multiples PTPs can dephosphorylate VEGFR2 and modulate its biological effects. Protein phosphatases often have domains that dictate their interaction partners or specific Senkyunolide I localization to subcellular compartments. DEP-1 and VE-PTP contain fibronectin type-III repeats implicated in cell adhesion. PTP1B and TC-PTP contain a C-terminal ER-anchoring motif. Shp1 and Shp2 have two SH2 domains that can bind phosphotyrosine residues and control activation of its PTP domain. PTP-MEG2 contains an N-terminal Sec14p-homology domain that targets this PTP to secretory vesicles. Open in a separate window Fig. 2 Summary of.