VE-PTP controls blood vessel development by balancing Tie-2 activity

Max-Planck-Institute of Molecular Biomedicine, D-48149 Münster, Germany.
The Journal of Cell Biology (Impact Factor: 9.83). 06/2009; 185(4):657-71. DOI: 10.1083/jcb.200811159
Source: PubMed


Vascular endothelial protein tyrosine phosphatase (VE-PTP) is an endothelial-specific receptor-type tyrosine phosphatase that associates with Tie-2 and VE-cadherin. VE-PTP gene disruption leads to embryonic lethality, vascular remodeling defects, and enlargement of vascular structures in extraembryonic tissues. We show here that antibodies against the extracellular part of VE-PTP mimic the effects of VE-PTP gene disruption exemplified by vessel enlargement in allantois explants. These effects require the presence of the angiopoietin receptor Tie-2. Analyzing the mechanism we found that anti-VE-PTP antibodies trigger endocytosis and selectively affect Tie-2-associated, but not VE-cadherin-associated VE-PTP. Dissociation of VE-PTP triggers the activation of Tie-2, leading to enhanced endothelial cell proliferation and enlargement of vascular structures through activation of Erk1/2. Importantly, the antibody effect on vessel enlargement is also observed in newborn mice. We conclude that VE-PTP is required to balance Tie-2 activity and endothelial cell proliferation, thereby controlling blood vessel development and vessel size.

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    • "PTPRJ (DEP-1/CD148), which corresponds to the Suppressor of colon cancer 1 (Scc1) gene (Ruivenkamp et al., 2002) dephosphorylates the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and CSF1R/Met growth factor RTKs (Chabot et al., 2009; Palka et al., 2003; Tarcic et al., 2009). PTPRB (VE-PTP) regulates Tie-2 (Winderlich et al., 2009), and PTPRO regulates TrkC and Eph RTKs (Hower et al., 2009; Shintani et al., 2006). Type III RPTPs can be tyrosine-phosphorylated on a C-terminal YxNF (F = hydrophobic) motif, and this causes activation of Src-family tyrosine kinases (SFKs) (Murata et al., 2010). "
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    ABSTRACT: We developed a screening method for orphan receptor ligands, in which cell-surface proteins are expressed in Drosophila embryos from GAL4-dependent insertion lines and ligand candidates identified by the presence of ectopic staining with receptor fusion proteins. Stranded at second (Sas) binds to the receptor tyrosine phosphatase Ptp10D in embryos and in vitro. Sas and Ptp10D can interact in trans when expressed in cultured cells. Interactions between Sas and Ptp10D on longitudinal axons are required to prevent them from abnormally crossing the midline. Sas is expressed on both neurons and glia, whereas Ptp10D is restricted to CNS axons. We conducted epistasis experiments by overexpressing Sas in glia and examining how the resulting phenotypes are changed by removal of Ptp10D from neurons. We find that neuronal Ptp10D restrains signaling by overexpressed glial Sas, which would otherwise produce strong glial and axonal phenotypes.
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    • "A recent study has demonstrated in mouse that the dissociation of Ve-ptp from VE-cadherin is a prerequisite for the destabilization of EC contacts and for the opening of endothelial junctions [26]. Furthermore in vitro data have demonstrated a role of Ve-ptp in fine-tuning the activity of two tyrosine kinases which play an important role in vascular morphogenesis and in angiogenic/remodeling processes such as Tie-2 and Vegfr2 [27], [28]. "
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    • "Negative regulation of these and other PTPRJ targets may be important for tumor suppression, because mouse PTPRJ corresponds to the Suppressor of colon cancer1 (Scc1) gene (Ruivenkamp et al., 2002). Two other Type III RPTPs, PTPRB (VE-PTP) and PTPRO, negatively regulate the angiopoietin receptor Tie-2 and the NT-3 receptor TrkC, respectively (Hower et al., 2009; Winderlich et al., 2009). "
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