c-ABL modulates MAP kinases activation downstream of VEGFR-2 signaling by direct phosphorylation of the adaptor proteins GRB2 and NCK1

Anselmi, Francesca; Orlandini, Maurizio; Rocchigiani, Marina; Clemente, Caterina De; Salameh, Ahmad; Lentucci, Claudia; Oliviero, Salvatore; Galvagni, Federico

doi:10.1007/s10456-012-9252-6

Cited by 31 publications

(19 citation statements)

References 51 publications

(64 reference statements)

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“…To assess a potential role for the Abl kinases in the regulation of endothelial barrier function, we initially evaluated Abl kinase activity following treatment of human microvascular endothelial cells (HMVECs) with the permeability-inducing factors VEGF, thrombin, and histamine. In agreement with previous findings in human umbilical vein endothelial cells (HUVECs) [28,30,31], stimulation of HMVECs with VEGF resulted in Abl kinase activation, as assessed by the phosphorylation of CrkL at tyrosine (Y) 207, an Abl-specific phosphorylation site [32] (Figure 1A ), which was prevented by pre-treatment with the ATP-competitive Abl kinase inhibitor imatinib. Interestingly, pre-treatment with the Src kinase inhibitor su6656 partially blocked Abl kinase activation in response to VEGF stimulation (Figure 1B ), suggesting that the Abl kinases may act downstream of Src family kinases in VEGF-mediated signaling.…”

Section: Resultssupporting

confidence: 91%

Abl Family Kinases Regulate Endothelial Barrier Function In Vitro and in Mice

Chislock

Pendergast

2013

PLoS ONE

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The maintenance of endothelial barrier function is essential for normal physiology, and increased vascular permeability is a feature of a wide variety of pathological conditions, leading to complications including edema and tissue damage. Use of the pharmacological inhibitor imatinib, which targets the Abl family of non-receptor tyrosine kinases (Abl and Arg), as well as other tyrosine kinases including the platelet-derived growth factor receptor (PDGFR), Kit, colony stimulating factor 1 receptor (CSF1R), and discoidin domain receptors, has shown protective effects in animal models of inflammation, sepsis, and other pathologies characterized by enhanced vascular permeability. However, the imatinib targets involved in modulation of vascular permeability have not been well-characterized, as imatinib inhibits multiple tyrosine kinases not only in endothelial cells and pericytes but also immune cells important for disorders associated with pathological inflammation and abnormal vascular permeability. In this work we employ endothelial Abl knockout mice to show for the first time a direct role for Abl in the regulation of vascular permeability in vivo. Using both Abl/Arg-specific pharmacological inhibition and endothelial Abl knockout mice, we demonstrate a requirement for Abl kinase activity in the induction of endothelial permeability by vascular endothelial growth factor both in vitro and in vivo. Notably, Abl kinase inhibition also impaired endothelial permeability in response to the inflammatory mediators thrombin and histamine. Mechanistically, we show that loss of Abl kinase activity was accompanied by activation of the barrier-stabilizing GTPases Rac1 and Rap1, as well as inhibition of agonist-induced Ca2+ mobilization and generation of acto-myosin contractility. In all, these findings suggest that pharmacological targeting of the Abl kinases may be capable of inhibiting endothelial permeability induced by a broad range of agonists and that use of Abl kinase inhibitors may have potential for the treatment of disorders involving pathological vascular leakage.

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Section: Resultssupporting

confidence: 91%

Abl Family Kinases Regulate Endothelial Barrier Function In Vitro and in Mice

Chislock

Pendergast

2013

PLoS ONE

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“…It binds phosphorylated insulin receptor substrate 1 and subsequently activates the MAPK pathway via Ras in response to insulin [30]. This gene is also involved in vascular endothelial growth factor signalling leading to angiogenesis, which is characteristic of proliferative diabetic retinopathy [31]. GRB2 encodes two transcripts in humans [32].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene

et al. 2015

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“…VEGF‐dependent angiogenesis requires p38MAPK activation and this response is dependent on the VEGFR2 co‐receptor neuropilin‐1, along with the VEGFR2 co‐receptor neuropilin‐1, for VEGF‐dependent angiogenesis . Furthermore, it has been reported that the VEGFR2‐dependent phosphorylation of Nck requires the c‐Abl tyrosine kinase .…”

Section: Vegfr2‐dependent Signalling Pathwaysmentioning

confidence: 99%

VEGFA and tumour angiogenesis

2013

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In this review we summarize the current understanding of signal transduction downstream of vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2, and the relationship between these signal transduction pathways and the hallmark responses of VEGFA, angiogenesis and vascular permeability. These physiological responses involve a number of effectors, including extracellular signal‐regulated kinases (ERKs), Src, phosphoinositide 3 kinase (PI3K)/Akt, focal adhesion kinase (FAK), Rho family GTPases, endothelial NO and p38 mitogen‐activated protein kinase (MAPK). Several of these factors are involved in the regulation of both angiogenesis and vascular permeability. Tumour angiogenesis primarily relies on VEGFA‐driven responses, which to a large extent result in a dysfunctional vasculature. The reason for this remains unclear, although it appears that certain aspects of the VEGFA‐stimulated angiogenic milieu (high level of microvascular density and permeability) promote tumour expansion. The high degree of redundancy and complexity of VEGFA‐driven tumour angiogenesis may explain why tumours commonly develop resistance to anti‐angiogenic therapy targeting VEGFA signal transduction.

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c-ABL modulates MAP kinases activation downstream of VEGFR-2 signaling by direct phosphorylation of the adaptor proteins GRB2 and NCK1

Cited by 31 publications

References 51 publications

Abl Family Kinases Regulate Endothelial Barrier Function In Vitro and in Mice

Abl Family Kinases Regulate Endothelial Barrier Function In Vitro and in Mice

Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene

VEGFA and tumour angiogenesis

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