Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors

Abstract

VE-cadherin is an essential adhesion molecule in endothelial adherens junctions, and the integrity of these complexes is thought to be regulated by VE-cadherin tyrosine phosphorylation. We have previously shown that adrenomedullin (AM) blockade correlates with elevated levels of phosphorylated VE-cadherin (pVE-cadherinY731) in endothelial cells, associated with impaired barrier function and a persistent increase in vascular endothelial cell permeability. However, the mechanism underlying this effect is unknown. In this article, we demonstrate that the AM-mediated dephosphorylation of pVE-cadherinY731 takes place through activation of the tyrosine phosphatase SHP-2, as judged by the rise of its active fraction phosphorylated at tyrosine 542 (pSHP-2Y542) in HUVECs and glioblastoma-derived-endothelial cells. Both pre-incubation of HUVECs with SHP-2 inhibitors NSC-87877 and SHP099 and SHP-2 silencing hindered AM-induced dephosphorylation of pVE-cadherinY731 in a dose dependent-manner, showing the role of SHP-2 in the regulation of endothelial cell contacts. Furthermore, SHP-2 inhibition impaired AM-induced HUVECs differentiation into cord-like structures in vitro and impeded AM-induced neovascularization in in vivo Matrigel plugs bioassays. Subcutaneously transplanted U87-glioma tumor xenograft mice treated with AM-receptors-blocking antibodies showed a decrease in pSHP-2Y542 associated with VE-cadherin in nascent tumor vasculature when compared to control IgG-treated xenografts.Our findings show that AM acts on VE-cadherin dynamics through pSHP-2Y542 to finally modulate cell-cell junctions in the angiogenesis process, thereby promoting a stable and functional tumor vasculature.

Modulation of Activity of Salivary Adrenomedullin by pH

“…Our study further strengthens the findings of Allaker & colleagues 17 in 1999 and Groschl 8 in 2009 that ADM shows antimicrobial effects against Gram-positive and Gram-negative bacteria.…”

“…Moreover, antimicrobial activity of ADM was not as efficient against S. aureus as against E. coli. It has been demonstrated that ADM has high affinity with E. coli lipopolysaccharide (LPS) 21 and therefore, it is expected that Gram-negative bacteria would be more susceptible to killing than Gram-positive bacteria 17 . A similar trend was observed in this study.…”

The Crosstalk between the Blood–Brain Barrier Dysfunction and Neuroinflammation after General Anaesthesia

“…The ECs are modified squamous epithelial cells of mesodermal origin participating in the formation of the vessel wall, anchored to the basement membrane with the help of cell adhesion molecules [ 27 ]. The structure and function of ECs on the BBB differ from those of other tissues ( Figure 2 ), the existence of polarity in BBB ECs controls the directional movement of ions, molecules, and immune cells from the circulation to the CNS [ 28 ].…”

“…In addition, vascular endothelial calcium adhesin resides between ECs ( Figure 2 ); it regulates the shape, polarity, and lumen formation of ECs and is involved in the maintenance of vascular integrity and permeability through intracellular signal pathways and transcription factors as well as regulating ECs transcription and protecting ECs from apoptosis [ 34 , 35 ], which plays a key role in maintaining the integrity of BBB ECs [ 27 ].…”

Adrenomedullin induces cisplatin chemoresistance in ovarian cancer through reprogramming of glucose metabolism

“…[ 12 , 19 ] Studies have shown that ADM can promote the proliferation of tumor cells, reduce the apoptosis rate of tumor cells, help tumor cells escape immune surveillance, and promote tumor angiogenesis. [ 19 , 20 ] There are significant differences in the expression of ADM in malignant and benign ovarian tumor tissues and normal ovarian tissue, suggesting that ADM is mainly produced by the ovarian malignant tumor tissues. ADM can be used as an indicator of malignant degree and poor prognosis of ovarian cancer, which is helpful for the diagnosis of high-risk patients in the early stage.…”