Receptor Chimeras Indicate That the Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) Modulates Mitogenic Activity of VEGFR-2 in Endothelial Cells

Rahimi, Nader; Dayanir, Volkan; Lashkari, Kameran

doi:10.1074/jbc.m000528200

Cited by 207 publications

(244 citation statements)

References 33 publications

(37 reference statements)

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“…It shows a temporal expression pattern in the inner neural retina that is distinct from VEGF (Feeney et al, 2003). Unlike VEGF, PlGF binds selectively to VEGFR-1 and thus its ability to activate tyrosine phosphorylation of VEGFR-2 is limited (VEGFR-1 may still elicit its role in angiogenesis by heterodimerization with VEGFR-2 and VEGFR-3) (Rahimi et al, 2000;Autiero et al, 2003;Dixelius et al, 2003). PlGF apparently does not lead to increased angiogenesis in response to hypoxia (Clauss et al, 1996;Cao et al, 1997;Shibuya et al, 1999;Simpson et al, 1999).…”

Section: Implications For Prevention and Treatment Of Ropmentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

598

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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Section: Implications For Prevention and Treatment Of Ropmentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

598

527

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“…A soluble form of the extracellular domain of VEGFR-1 (sFlt-1) inhibits VEGF-induced migration and proliferation of human microvascular endothelial cells and HUVECs by forming inactive complexes with VEGF and VEGFR-2 (61,62). Two studies using chimeras of VEGFR-1 and VEGFR-2 have found that these chimeras suppress VEGFR-2-mediated proliferation, but not migration (63,64). Exchanging the juxtamembrane region of the VEGFR-2 with VEGFR-1 suppresses VEGFR-2-mediated signaling and migration (65).…”

Section: Vegf-induced Signal Transduction and Endothelial Functionmentioning

confidence: 99%

VEGF Receptor Signaling and Endothelial Function

Kliche¹,

2001

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“…VEGF activates a broad spectrum of biological responses in endothelial cells, including cell proliferation, migration, survival, differentiation and permeability to macromolecules (Waltenberger et al, 1994;Neufeld et al, 1996;Rahimi et al, 2000;Suarez and Ballmer-Hofer, 2001). Although VEGFR-1 and VEGFR-2 are structurally highly similar, their mechanisms of angiogenic signal transduction relay appear to differ drastically from each other.…”

Section: Introductionmentioning

confidence: 99%

“…Despite having these similarities with other RTKs, the ligand-dependent stimulation of VEGFR-1 results in no significant autophosphorylation of VEGFR-1 itself or induces proliferation of endothelial cells (Waltenberger et al, 1994;Rahimi et al, 2000). However, VEGFR-1 may stimulate biological responses in endothelial cells potentially by heterodimerizing with VEGFR-2 (Kanno et al, 2000;Rahimi et al, 2000;Autiero et al, 2003). VEGFR-1 activation in some nonendothelial cells is reported to stimulate cell migration and proliferation (Clauss et al, 1996;Athanassiades et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…VEGF binds to multiple endothelial cell surface receptors, including VEGFR-1, VEGFR-2 and Neuropilin-1 and 2 (Soker et al, 1998;Neufeld et al, 1999;Lee et al, 2002). We have recently constructed a chimeric receptor containing the extracellular domain of human CSF-1R/c-fms, fused with the transmembrane and the cytoplasmic domains of human VEGFR-1 (Rahimi et al, 2000). This model permitted us to dissect the function of VEGFR-1 in endothelial cells by selectively stimulating the receptor with CSF-1.…”

Section: Introductionmentioning

confidence: 99%

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Substitution of C-terminus of VEGFR-2 with VEGFR-1 promotes VEGFR-1 activation and endothelial cell proliferation

et al. 2004

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VEGFR-1 is devoid of ligand-dependent tyrosine autophosphorylation and its activation is not associated with proliferation of endothelial cells. The molecular mechanism responsible for this characteristic of VEGFR-1 is not known. In this study, we show that VEGFR-1 is devoid of ligand-dependent downregulation and failed to stimulate intracellular calcium release, cell migration and angiogenesis in vitro. To understand the molecular mechanisms responsible for the poor tyrosine autophosphorylation of VEGFR-1, we have either deleted the carboxyl terminus of VEGFR-1 or exchanged it with the carboxyl terminus of VEGFR-2. The deletion of carboxyl terminus of VEGFR-1 did not reverse its defective ligand-dependent autophosphorylation. The carboxyl terminus-swapped VEGFR-1, however, displayed ligand-dependent autophosphorylation, downregulation and also conveyed strong mitogenic responses. Thus, the carboxyl tail of VEGFR-1 restrains the ligand-dependent kinase activation and downregulation of VEGFR-1 and its ability to convey the angiogenic responses in endothelial cells.

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Receptor Chimeras Indicate That the Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) Modulates Mitogenic Activity of VEGFR-2 in Endothelial Cells

Cited by 207 publications

References 33 publications

Vascular endothelial growth factor in eye disease

Vascular endothelial growth factor in eye disease

VEGF Receptor Signaling and Endothelial Function

Substitution of C-terminus of VEGFR-2 with VEGFR-1 promotes VEGFR-1 activation and endothelial cell proliferation

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