VEGF (vascular endothelial growth factor) regulates neovascularization through binding to its receptor KDR (kinase insert domain-containing receptor; VEGF receptor-2). We recently identified a catalytically inactive PLA(2) (phospholipase A(2)) homologue (KDR-bp) in the venom of eastern cottonmouth (Agkistrodon piscivorus piscivorus) as a third KDR-binding protein, in addition to VEGF(165) and tissue inhibitor of metalloproteinase-3. KDR-bp binds to the extracellular domain of KDR with a K(d) of 10(-8) M, resulting in specific blockade of endothelial cell growth induced by VEGF(165). Inactive PLA(2) homologues are widely distributed in the venoms of Viperidae snakes and are known to act as myotoxins. In the present study, we demonstrated that KDR-binding ability is a common characteristic for inactive PLA(2) homologues in snake venom, but not for active PLA(2)s such as neurotoxic and platelet aggregation-modulating PLA(2)s. To understand better the KDR and KDR-bp interaction, we resolved the binding region of KDR-bp using eight synthetic peptides designed based on the structure of KDR-bp. A synthetic peptide based on the structure of the C-terminal loop region of KDR-bp showed high affinity for KDR, but other peptides did not, suggesting that the C-terminal loop region of KDR-bp is involved in the interaction with KDR. The results of the present study provide insight into the binding of inactive PLA(2) homologues to KDR, and may also assist in the design of novel anti-KDR molecules for anti-angiogenic therapy.

Download full-text PDF

Source
http://dx.doi.org/10.1042/BJ20080078DOI Listing

Publication Analysis

Top Keywords

inactive pla2
16
c-terminal loop
12
loop region
12
pla2 homologues
12
region kdr-bp
12
catalytically inactive
8
phospholipase homologue
8
vascular endothelial
8
endothelial growth
8
growth factor
8

Similar Publications

Phagocytosis, an essential process for host defense, requires the coordination of a variety of signaling reactions. MT-II, an enzymatically inactive Lys49 phospholipase A (PLA) homolog, and MT-III, a catalytically-active Asp49 PLA, are known to activate phagocytosis in macrophages. In this study, the signaling pathways mediating phagocytosis, focusing on protein kinases, were investigated.

View Article and Find Full Text PDF
Article Synopsis
  • The biosynthesis of GPI-anchored proteins in Trypanosoma brucei requires fatty acid remodeling of GPI precursors before protein transfer in the endoplasmic reticulum.
  • Researchers identified the gene Tb927.7.6110, which encodes a protein necessary for GPI-phospholipase A2 (GPI-PLA2) activity in the parasite's procyclic form.
  • The absence of this gene in mutant cells led to reduced fatty acid remodeling and smaller GPI anchor sidechains, but this was restored by reintroducing Tb927.7.6110, indicating its critical role in the process.
View Article and Find Full Text PDF

Verticillium longisporum phospholipase VlsPLA is a virulence factor that targets host nuclei and modulates plant immunity.

Mol Plant Pathol

September 2023

Department of Forest Mycology and Plant Pathology, Swedish University of Agricultural Sciences, Uppsala Biocenter, Uppsala, Sweden.

Phospholipase A (PLA ) is a lipolytic enzyme that hydrolyses phospholipids in the cell membrane. In the present study, we investigated the role of secreted PLA (VlsPLA ) in Verticillium longisporum, a fungal phytopathogen that mostly infects plants belonging to the Brassicaceae family, causing severe annual yield loss worldwide. Expression of the VlsPLA gene, which encodes active PLA , is highly induced during the interaction of the fungus with the host plant Brassica napus.

View Article and Find Full Text PDF

Catalytically Active Snake Venom PLA Enzymes: An Overview of Its Elusive Mechanisms of Reaction.

J Med Chem

April 2023

LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal.

Snake venom-secreted phospholipase A (svPLA) enzymes, both catalytically active and inactive, are a central component in envenoming. These are responsible for disrupting the cell membrane's integrity, inducing a wide range of pharmacological effects, such as the necrosis of the bitten limb, cardiorespiratory arrest, edema, and anticoagulation. Although extensively characterized, the reaction mechanisms of enzymatic svPLA are still to be thoroughly understood.

View Article and Find Full Text PDF

Lyso-PAF, a biologically inactive phospholipid, contributes to RAF1 activation.

Mol Cell

June 2022

Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA; Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. Electronic address:

Phospholipase A2, group VII (PLA2G7) is widely recognized as a secreted, lipoprotein-associated PLA2 in plasma that converts phospholipid platelet-activating factor (PAF) to a biologically inactive product Lyso-PAF during inflammatory response. We report that intracellular PLA2G7 is selectively important for cell proliferation and tumor growth potential of melanoma cells expressing mutant NRAS, but not cells expressing BRAF V600E. Mechanistically, PLA2G7 signals through its product Lyso-PAF to contribute to RAF1 activation by mutant NRAS, which is bypassed by BRAF V600E.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!