Expression of receptor-type protein tyrosine phosphatase in developing and adult renal vasculature

Abstract

Renal vascular development is a coordinated process that requires ordered endothelial cell proliferation, migration, intercellular adhesion, and morphogenesis. In recent decades, studies have defined the pivotal role of endothelial receptor tyrosine kinases (RPTKs) in the development and maintenance of renal vasculature. However, the expression and the role of receptor tyrosine phosphatases (RPTPs) in renal endothelium are poorly understood, though coupled and counterbalancing roles of RPTKs and RPTPs are well defined in other systems. In this study, we evaluated the promoter activity and immunolocalization of two endothelial RPTPs, VE-PTP and PTPμ, in developing and adult renal vasculature using the heterozygous LacZ knock-in mice and specific antibodies. In adult kidneys, both VE-PTP and PTPμ were expressed in the endothelium of arterial, glomerular, and medullary vessels, while their expression was highly limited in peritubular capillaries and venous endothelium. VE-PTP and PTPμ promoter activity was also observed in medullary tubular segments in adult kidneys. In embryonic (E12.5, E13.5, E15.5, E17.5) and postnatal (P0, P3, P7) kidneys, these RPTPs were expressed in ingrowing renal arteries, developing glomerular microvasculature (as early as the S-shaped stage), and medullary vessels. Their expression became more evident as the vasculatures matured. Peritubular capillary expression of VE-PTP was also noted in embryonic and postnatal kidneys. Compared to VE-PTP, PTPμ immunoreactivity was relatively limited in embryonic and neonatal renal vasculature and evident immunoreactivity was observed from the P3 stage. These findings indicate 1) VE-PTP and PTPμ are expressed in endothelium of arterial, glomerular, and medullary renal vasculature, 2) their expression increases as renal vascular development proceeds, suggesting that these RPTPs play a role in maturation and maintenance of these vasculatures, and 3) peritubular capillary VE-PTP expression is down-regulated in adult kidneys, suggesting a role of VE-PTP in the development of peritubular capillaries.

A Small Molecule Inhibitor of VE-PTP Activates Tie2 in Schlemm's Canal Increasing Outflow Facility and Reducing Intraocular Pressure

“…45,46 Other single cell RNAseq studies report the presence of VE-PTP expression in isolated lymphatic cell clusters, however, VE-PTP protein expression in vivo appears distinctly absent from lymphatic endothelial cells in multiple tissues in several studies, including the present one. 33,42,[47][48][49] One exception appears to be VE-PTP protein expression in cultured human dermal lymphatic endothelial cells. 50,51 Perhaps reflecting the hybrid nature of the SC endothelium, VE-PTP was not homogeneously expressed when assessed by reporter gene expression and expression levels appeared generally lower than in vascular endothelial cells.…”

The protein tyrosine phosphatase DEP-1/PTPRJ promotes breast cancer cell invasion and metastasis

“…Indeed, MDA-MB-231 cells have lost E-cadherin expression and their adherens junctions, which is a potential site of interaction for DEP-1 with its receptor tyrosine kinase substrates, such as EGFR. 19,77 shScramble shDEP-1 The constitutive activation of downstream proliferative pathways, such as K-Ras in MDA-MB-231 cells, 78 might also overcome the negative regulation of growth-promoting receptors by DEP-1. In addition, polymorphisms and mutations in the DEP-1 gene could perhaps alter the growth-suppressive functions of DEP-1, while still allowing Src activation and the manifestation of its proinvasive functions.…”

“…3,[9][10][11][12] Increased expression of DEP-1 has been associated with the negative regulation of cell proliferation and transformation, and with the induction of cell differentiation. 8,[13][14][15][16][17][18] Consistent with these roles and with the enriched localization of DEP-1 at adherens junctions, 19 many substrates of DEP-1 are cell-cell adhesion proteins [20][21][22] and receptor tyrosine kinases. 13,[22][23][24][25][26][27] In contrast, DEP-1 was also shown to regulate positively various biological functions, including B-cell and macrophage development, platelet activation, cell adhesion and angiogenesis, through its ability to dephosphorylate the inhibitory tyrosine residue of Src family kinases (Y529 in Src) and allow their autophosphorylation and activation (Y418 in Src).…”

Regulation of Endothelial Adherens Junctions by Tyrosine Phosphorylation

“…Dep1 was also shown to be expressed in the endothelium in vivo and to colocalize with VE-cadherin [ 207 ], but its role is not completely understood. Homozygous expression of a mutant Dep1 that lacks the phosphatase domain is embryonically lethal.…”