An Antibody Reactive with Domain 4 of the Platelet-derived Growth Factor β Receptor Allows BB Binding while Inhibiting Proliferation by Impairing Receptor Dimerization

Shul'man, T. S.; Sauer, Frederic G.; Jackman, Robin M.; Chang, Chung Nan; Landolfi, Nicholas F.

doi:10.1074/jbc.272.28.17400

Cited by 20 publications

(13 citation statements)

References 21 publications

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“…In all cases, these contacts are mediated by membrane-proximal Ig-like domains; domains 4 and/or 5 in PDGFR and Kit, domain 7 and perhaps 4 in VEGFR-2. This concept is also well supported by earlier published biochemical data for PDGF and VEGF receptors (47,51,(63)(64)(65)(66). Thus, by maintaining a rigid conformation of the ligand-bound ECD, homotypic interaction between receptor monomers serves to properly position the intracellular kinase domains in active receptor dimers (Fig.…”

Section: The Role Of the Extracellular Domain In Receptor Activationsupporting

confidence: 70%

“…Extensive mutagenesis and monoclonal antibody mapping was used to biochemically characterize receptor-ligand interaction (46)(47)(48)(49)(50)(51). Distinct Ig-like subdomains and the linkers connecting them form high-affinity binding sites for the cognate ligands as shown in high-resolution structures of FGF family receptors (52)(53)(54)(55)(56).…”

Section: The Role Of the Extracellular Domain In Receptor Activationmentioning

confidence: 99%

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Structure and function of VEGF receptors

2009

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SummaryVascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development and homeostasis. VEGFs are predominantly produced by endothelial, hematopoietic, and stromal cells in response to hypoxia and upon stimulation by growth factors such as transforming growth factor b (TGFb), interleukins, or platelet-derived growth factors (PDGFs). VEGFs specifically interact with one or several receptor tyrosine kinases (RTKs), VEGF receptor-1, -2, and -3 (VEGFR-1, -2, -3), and with distinct coreceptors such as neuropilins or heparan sulfate glycosaminoglycans. VEGF receptors are classified as type V RTKs whose extracellular domains consists of seven immunoglobulin-like (Ig-like) domains. VEGF receptors are activated upon ligand-mediated dimerization. However, little was known about the mechanism of receptor activation at the structural level until recently. New data published by several labs for VEGF and the related type III RTKs now suggest that both ligand-receptor as well as homotypic receptor-receptor interactions stabilize ligand-induced receptor dimers. These data support the idea that structural changes induced in the extracellular domain upon ligand binding instigate transmembrane signaling by properly positioning the intracellular kinase domains in active receptor dimers.2009 IUBMB IUBMB Life, 61(9): 915-922, 2009

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Section: The Role Of the Extracellular Domain In Receptor Activationsupporting

confidence: 70%

Section: The Role Of the Extracellular Domain In Receptor Activationmentioning

confidence: 99%

Structure and function of VEGF receptors

2009

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“…Some studies showed that monoclonal antibodies directed against the extracellular domain of the PDGF receptor can prevent binding of the PDGF ligand, thereby inhibiting mitogenic signaling (Heldin, 1997;Shulman et al, 1997). In a different strategy, BorkhamKamphorst et al (2004) produced a soluble PDGF receptor that was capable of reducing extracellular matrix deposition in the BDL model after daily administration for 14 days.…”

Section: Discussionmentioning

confidence: 99%

Local Inhibition of Liver Fibrosis by Specific Delivery of a Platelet-Derived Growth Factor Kinase Inhibitor to Hepatic Stellate Cells

Gonzalo¹,

Beljaars²,

Bovenkamp³

et al. 2007

J Pharmacol Exp Ther

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Liver fibrosis is characterized by excessive proliferation and activation of hepatic stellate cells (HSC), a process in which platelet-derived growth factor (PDGF) plays an important role. Inhibition of liver fibrosis via specific delivery of a PDGF kinase inhibitor to HSC might therefore be an attractive strategy. The HSC-selective carrier mannose-6-phosphate modified human serum albumin (M6PHSA) was equipped with a tyrosine kinase inhibitor, 4-chloro-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (PAP19) (an imatinib derivative), by means of the platinum-based universal linkage system (ULS). The antifibrotic activity of PAP19-M6PHSA was evaluated in culture-activated rat HSC and precision-cut liver slices from fibrotic rats. After 24-h incubation, both free inhibitor PAP19 and PAP19-M6PHSA showed potent activity, as determined by quantitative reverse transcription-polymerase chain reaction analysis of ␣-smooth muscle actin (␣SMA) and procollagen 1a1. Next, we examined the organ distribution and antifibrotic activity of PAP19-M6PHSA in bile duct-ligated (BDL) rats. Male Wistar rats at day 10 after BDL were administered a single dose of PAP19-M6PHSA and sacrificed at 2 h, 1 day, or 2 days afterward. The accumulation of PAP19-M6PHSA in the liver was quantified by high-performance liquid chromatography analysis (30% of the injected dose at 2 h) and detected in the liver by staining of the carrier. Liver drug levels were sustained at 24 and 48 h after the single dose. Furthermore, PAP19-M6PHSA reduced collagen deposition (Sirius red staining) and ␣SMA staining of activated HSC at these time points in comparison with saline-treated rats. We therefore conclude that delivery of a PDGF-kinase inhibitor to HSC is a promising technology to attenuate liver fibrogenesis.

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“…Further support for a role of the PDGF receptor Ig-like domain 4 in receptor dimerization, but not in direct ligand binding, has been provided through the recent characterization of monoclonal antibodies against Ig-like domain 4 of the PDGF ␤-receptor that block receptor signaling without affecting ligand binding (18,19). Ig-like domain 4 of the stem cell factor receptor has also been shown to be involved in receptor-receptor interactions (28).…”

Section: Discussionmentioning

confidence: 99%

Role of Immunoglobulin-like Domains 2–4 of the Platelet-derived Growth Factor α-Receptor in Ligand-Receptor Complex Assembly

Miyazawa

Bäckström

Leppänen

et al. 1998

Journal of Biological Chemistry

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Platelet-derived growth factor (PDGF) is a dimeric protein that exerts its effects through tyrosine kinase ␣-and ␤-receptors. The extracellular part of each receptor is composed of five Ig-like domains. Recombinant forms of ␣-receptor domains 1-4 (␣RD1-4), 1-3 (␣RD1-3), and 1 and 2 (␣RD1-2) were prepared after expression in Chinese hamster ovary cells and were used to study the assembly of soluble ligand-receptor complexes. When incubated with micromolar concentrations of PDGF, both ␣RD1-3 and ␣RD1-4 formed complexes of 1:2 molar composition, i.e. one dimeric PDGF molecule bound two soluble receptors. ␣RD1-3, in contrast to ␣RD1-4, formed detectable 1:1 complexes under conditions of ligand excess. ␣RD1-4 displayed an increased ability to form 1:2 complexes as compared with ␣RD1-3 under conditions of limiting concentrations of ligand. We thus conclude that Ig-like domain 4-mediated receptor-receptor interactions contribute to 1:2 PDGF⅐␣RD1-4 complex formation. Since ␣RD1-4 and ␣RD1-3 were equipotent in blocking binding of subnanomolar concentrations of PDGF to cell-surface receptors, we also conclude that this effect is predominantly achieved through formation of Ig-like domain 4-independent 1:1 ligand-receptor complexes. Finally, since ␣RD1-2 bound PDGF-BB with high affinity, whereas PDGF-AA was bound only with low affinity, we conclude that Ig-like domain 3 of the PDGF ␣-receptor contains epitopes of particular importance for PDGF-AA binding and that most of the PDGF-BB-binding epitopes reside in Ig-like domains 1 and 2.Platelet-derived growth factors (PDGFs) 1 are a family of disulfide-bonded dimeric isoforms of A-and B-chains with potent mitogenic activity on connective tissue cells, glia cells, and endothelial cells (reviewed in Ref. 1). PDGF has been implicated in a number of diseases involving proliferation of PDGFresponsive cells, such as atherosclerosis, restenosis, glomerulonephritis, and certain malignancies (2).PDGF A-and B-chains, which have ϳ60% identical amino acid sequences in their mature parts, form homo-and heterodimers that exert their cellular effects through two structurally related tyrosine kinase receptors, denoted ␣-and ␤-receptors (3). The A-chain binds only ␣-receptors, whereas the B-chain binds both ␣-and ␤-receptors.Crystallographic analysis of PDGF-BB revealed that the two subunits are arranged in an antiparallel manner (4). Each subunit consists of a tight cystine knot motif from which two loops (loops 1 and 3) point in one direction and one loop (loop 2) points in the other direction. As a consequence of the antiparallel arrangement of the dimer, loops 1 and 3 of one subunit are juxtaposed to loop 2 of the other subunit. Mutational analysis has mapped the receptor-binding amino acid residues mainly to loops 1 and 3, but loop 2 also contributes to some extent (4 -8).The dimeric PDGF molecule thus displays two receptor-binding regions, each one made up of epitopes derived from both subunits.Both PDGF ␣-and ␤-receptors consist of an extracellular part composed of five Ig-like domain...

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An Antibody Reactive with Domain 4 of the Platelet-derived Growth Factor β Receptor Allows BB Binding while Inhibiting Proliferation by Impairing Receptor Dimerization

Cited by 20 publications

References 21 publications

Structure and function of VEGF receptors

Structure and function of VEGF receptors

Local Inhibition of Liver Fibrosis by Specific Delivery of a Platelet-Derived Growth Factor Kinase Inhibitor to Hepatic Stellate Cells

Role of Immunoglobulin-like Domains 2–4 of the Platelet-derived Growth Factor α-Receptor in Ligand-Receptor Complex Assembly

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