A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit.

Matthews, William; Jordan, Craig T.; Gavin, Marc A.; Jenkins, Nancy A.; Copeland, Neal G.; Lemischka, Ihor R.

doi:10.1073/pnas.88.20.9026

Cited by 444 publications

(230 citation statements)

References 27 publications

(36 reference statements)

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“…Sections were stained for Ki67, a marker for cell proliferation, using an anti-Ki67 antibody (AbCam, Cambridge, Cambs, UK) with an ABC complex and chromogen kit which yielded a red stain when positive. The effect of the compounds on angiogenesis was assessed by staining for VEGFR-2 (AbCam), a marker for endothelial cells (Matthews et al, 1991;Terman et al, 1992). For this, sections were stained using a human VEGFR-2 antibody with a streptavidin peroxidase system with subsequent haemotoxylin counterstaining.…”

Section: Tumour Histologymentioning

confidence: 99%

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

et al. 2007

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Drugs that inhibit growth of tumours and their blood supply could have considerable therapeutic potential. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate (2-MeOE2bisMATE) has been shown to inhibit the proliferation of MCF-7 (ER+) breast cancer cells and angiogenesis in vitro. 2-MeOE2bisMATE and its analogue, 17-Cym-2-MeOE2MATE, were investigated for their ability to inhibit in vivo angiogenesis and tumour growth. The mouse Matrigel plug assay for angiogenesis was used to investigate the effect of compounds on neovascularisation and was quantified using a FITC-dextran injection technique. Nude mice bearing tumours derived from MCF-7 cells were used to assess efficacy on tumour growth. Tumour sections were stained for VEGFR-2 and Ki67 to assess tumour angiogenesis and cell proliferation respectively. Matrigel plugs supplemented with basic fibroblast growth factor resulted in increased neovascularisation over 7 days. Oral administration of 2-MeOE2bisMATE for 7 days at 10 or 50 mg kg À1 significantly reduced neovascularisation to or below control levels respectively. 17-Cym-2-MeOE2MATE at 20 mg kg À1 was equally effective. 2-MeOE2bisMATE, dosed daily for 21 days, caused a 52% reduction in tumour growth at 5 mg kg À1 and 38% regression at 20 mg kg À1 . 17-Cym-2-MeOE2MATE (20 mg kg À1 ) reduced tumour growth by 92%. Immunohistochemistry revealed a reduction in angiogenesis and proliferation. Matrigel plug and tumour imaging after FITC-dextran injection indicated that 2-MeOE2bisMATE caused a marked disruption of vasculature. These sulphamoylated oestrogen derivatives have been shown to be potent inhibitors of angiogenesis in vivo. This, together with their ability to inhibit tumour growth, indicates the potential of this new class of drugs for further development for cancer therapy.

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Section: Tumour Histologymentioning

confidence: 99%

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

et al. 2007

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“…Flt-1 and KDR/Flk-1 belong to a receptor gene family distantly related to Fms/Kit/PDGF receptor, and share 7-immunoglobulin (Ig)-like domains in the extracellular domain and a long kinase insert in the middle of the kinase domain (Shibuya et al, 1990;Matthews et al, 1991;Terman et al, 1992). Since the mRNAs of the Flt-1 and KDR/ Flk-1 are speci®cally expressed in the vascular endothelial cells (Jakeman et al, 1993;Eichmann et al, 1993;Kaipainen et al, 1993;Quinn et al, 1993;Yamane et al, 1994), VEGF has been considered to be in most cases only relevant to the vascular system.…”

Section: Introductionmentioning

confidence: 99%

VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells

1999

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“…Flt-1 and KDR/Flk-1 have common structural characteristics and share 7-Immunoglobulin (Ig)-like domains in the extracellular domain and a long kinase insert in the middle of the kinase domain (Shibuya et al, 1990;Matthews et al, 1991;Terman et al, 1992). Since the mRNAs on the Flt-1 and KDR/Flk-1 are speci®cally expressed in the vascular endothelial cells (Jakeman et al, 1993;Eichmann et al, 1993;Kaipainen et al, 1993;Quinn et al, 1993;Yamane et al, 1994), VEGF has been considered to be in most cases only relevant to the vascular system.…”

Section: Introductionmentioning

confidence: 99%

The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-γ pathway and partially induces mitotic signals in NIH3T3 fibroblasts

1997

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KDR/Flk-1 tyrosine kinase, one of the two receptors for Vascular Endothelial Growth Factor (VEGF) has been shown to generate the major part of mitotic signals in endothelial cells, although the mechanisms are poorly understood. Here we examined the processing and signal transduction of KDR/Flk-1. Both in endothelial cells and in NIH3T3 cells expressing KDR/Flk-1, an immature form of KDR/Flk-1 with a molecular mass of about 150 kDa was glycosylated to create a 200 kDa intermediate, and after further glycosylation a mature 230 kDa was expressed on the cell surface. Only this 230 kDa form was rapidly and transiently phosphorylated on tyrosine residues in the presence of VEGF. As a major substrate of KDR/Flk-1, PLC-g was found to be rapidly tyrosine-phosphorylated and associated with KDR/Flk-1 both in endothelial cells and NIH3T3 cells. Interestingly, however, a prompt activation of MAP kinase and subsequent strong mitotic signaling were generated only in the endothelial cell background. Activation of MAP kinase in NIH3T3 cells overexpressing KDR/Flk-1 showed a slower response as maximum levels were only attained after 20 min compared to 5 min in sinusoidal endothelial cells. These results suggest that the KDR/Flk-1 utilizes cell typespeci®c signal transduction pathway(s) for MAP kinase activation and the mitotic response in endothelial cells.

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A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit.

Cited by 444 publications

References 27 publications

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells

The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-γ pathway and partially induces mitotic signals in NIH3T3 fibroblasts

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