Functional Importance of Platelet-derived Growth Factor (PDGF) Receptor Extracellular Immunoglobulin-like Domains

Lokker, Nathalie A.; O'Hare, J P; Barsoumian, Arpy; Tomlinson, James; Ramakrishnan, Vanitha; Fretto, L J; Giese, Neill A.

doi:10.1074/jbc.272.52.33037

Cited by 53 publications

(50 citation statements)

References 37 publications

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“…Supporting such a mechanism is the evidence that PDGF-mediated dimerization of PDGF receptor extracellular domains requires receptor sequences that apparently do not contribute to PDGF binding (40,48,49). The proposed mechanism is sufficient for positive cooperativity to be observed with respect to PDGF concentration.…”

Section: Pdgf Receptor Binding Dimerization and Endocytosismentioning

confidence: 66%

Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts

Park

Schneider²,

Haugh

2003

Journal of Biological Chemistry

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Isoforms of the serine-threonine kinase Akt coordinate multiple cell survival pathways in response to stimuli such as platelet-derived growth factor (PDGF). Activation of Akt is a multistep process, which relies on the production of 3 -phosphorylated phosphoinositide (PI) lipids by PI 3-kinases. To quantitatively assess the kinetics of PDGF receptor/PI 3-kinase/Akt signaling in fibroblasts, a systematic study of this pathway was performed, and a mechanistic mathematical model that describes its operation was formulated. We find that PDGF receptor phosphorylation exhibits positive cooperativity with respect to PDGF concentration, and its kinetics are quantitatively consistent with a mechanism in which receptor dimerization is initially mediated by the association of two 1:1 PDGF/PDGF receptor complexes. Receptor phosphorylation is transient at high concentrations of PDGF, consistent with the loss of activated receptors upon endocytosis. By comparison, Akt activation responds to lower PDGF concentrations and exhibits more sustained kinetics. Further analysis and modeling suggest that the pathway is saturated at the level of PI 3-kinase activation, and that the p110␣ catalytic subunit of PI 3-kinase contributes most to PDGFstimulated 3 -PI production. Thus, at high concentrations of PDGF the kinetics of 3 -PI production are limited by the turnover rate of these lipids, while the Akt response is additionally influenced by the rate of Akt deactivation.Platelet-derived growth factor (PDGF) 1 is a polypeptide mitogen of broad specificity, one of the earliest and most potent serum factors to be isolated (1). Beyond signaling of proliferation, PDGF acts as a strong chemoattractant during wound healing and can mediate protection from apoptosis in response to serum withdrawal and certain stress stimuli (2, 3). Three forms of PDGF have been studied extensively. They are composed of disulfide-bonded homo-and heterodimers of A and B chains, of which PDGF-BB is the best characterized. There are two structurally related PDGF receptors, ␣ and ␤, which exhibit different affinities for the A chain but roughly equivalent affinities for the B chain (4, 5). More recently, PDGF-C and -D isoforms, which form homodimers, have also been identified; these too exhibit different affinities for PDGF ␣-and ␤-receptors (6 -8).PDGF receptors belong to the well studied class of signal transducers collectively known as receptor-tyrosine kinases (9, 10). As with other receptors of this class, ligand-induced dimerization of PDGF receptors activates their intrinsic kinase domains, which catalyze the autophosphorylation of the receptors on multiple intracellular tyrosine residues in trans (11-13). The phosphorylated receptor may then act as a scaffold for specific binding interactions with cytosolic signal transduction enzymes and adaptor proteins (14). Among the most important of these are isoforms of phosphoinositide (PI) 3-kinase, which phosphorylate phosphatidylinositol (PtdIns) lipids in cell membranes to produce the 3Ј-PI second messengers PtdI...

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Section: Pdgf Receptor Binding Dimerization and Endocytosismentioning

confidence: 66%

Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts

Park

Schneider²,

Haugh

2003

Journal of Biological Chemistry

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“…Several transcription factors contain prolinerich regions, which are known to act as transactivation or repression sites (27,28). Vascular endothelial growth factor receptor (29 -32) and platelet-derived growth factor receptor (33,34) have regions homologous with the Ig-like domain of MIDORI. These domains consist of a heparin-or agonist-binding site and are thought to be essential for receptor dimerization.…”

Section: Discussionmentioning

confidence: 99%

A Novel Myocyte-specific Gene MidoriPromotes the Differentiation of P19CL6 Cells into Cardiomyocytes

Hosoda¹,

Monzen²,

Hiroi³

et al. 2001

Journal of Biological Chemistry

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Although several cardiac-specific transcription factors have been shown to play vital roles in various steps during the heart formation, the precise mechanism of the early stage of cardiogenesis has yet to be elucidated. By differential display technique, we tried to identify molecules that are expressed earlier than cardiac transcription factors such as CSX/NKX2-5 and GATA-4 and are involved in cardiomyocyte differentiation using the P19CL6 cell line, which efficiently differentiates into cardiomyocytes when treated with dimethyl sulfoxide. We isolated a novel gene designated Midori. Its deduced amino acid sequence contained an ATP/GTP-binding site, Ig-like domain, and Kringle-like domain. Northern blot analysis revealed that expression of Midori was restricted to the fetal and adult heart and adult skeletal muscle in mice. In whole mount in situ hybridization, Midori was expressed in cardiac crescent and developing heart but not in somites. The MIDORI protein was localized in the nucleus and overexpression of Midori induced expression of endogenous Midori itself, suggesting that MIDORI may act as a transcriptional regulator. Permanent P19CL6 cell lines overexpressing Midori more efficiently differentiated into cardiomyocytes than did parental cells, whereas those overexpressing the antisense Midori less efficiently differentiated. These results suggest that Midori may promote the differentiation of P19CL6 into cardiomyocytes.

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“…All sera found positive for anti-PDGFRa autoantibodies by direct ELISA, including 16 samples found positive and 8 found negative by the competitive ELISA, contained ROS-inducing IgG, except SSc serum sample 24, which was negative on the competitive ELISA. Conversely, the 4 sera (samples [25][26][27][28] found negative on the direct ELISA did not contain ROSinducing IgG.…”

Section: Epitope Specificity Of Anti-pdgfra Autoantibodies In Sscmentioning

confidence: 99%

Epitope Specificity Determines Pathogenicity and Detectability of Anti–Platelet‐Derived Growth Factor Receptor α Autoantibodies in Systemic Sclerosis

Moroncini

Grieco

Nacci

et al. 2015

Arthritis & Rheumatology

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Objective. To identify the epitopes recognized by autoantibodies targeting platelet-derived growth factor receptor a (PDGFRa) in systemic sclerosis (SSc) and develop novel assays for detection of serum antiPDGFRa autoantibodies.Methods. Epstein-Barr virus-immortalized B cells from 1 patient with SSc (designated PAM) were screened for expression of IgG binding to PDGFRa and induction of reactive oxygen species in fibroblasts. The variable regions of anti-PDGFRa IgG were cloned into an IgG expression vector to generate distinct recombinant human monoclonal autoantibodies (mAb), which were characterized by binding and functional assays. The epitopes of anti-PDGFRa recombinant human mAb were defined by molecular docking, surface plasmon resonance binding assays, screening of a conformational peptide library spanning the PDGFRa extracellular domains, and expression analyses of alanine-scanned PDGFRa mutants. Direct or competitive enzyme-linked immunosorbent assays were established to detect all serum anti-PDGFRa autoantibodies or, selectively, the agonistic ones.Results. Three types of anti-PDGFRa recombinant human mAb, with the same V H but distinct V L chains, were generated. Nonagonistic V H PAM-V k 13B8 recognized 1 linear epitope, whereas agonistic V H PAM-V l 16F4 and V H PAM-V k 16F4 recognized 2 distinct conformational epitopes. Serum anti-PDGFRa antibodies were detected in 66 of 70 patients with SSc, 63 of 130 healthy controls, 11 of 26 patients with primary Raynaud's phenomenon (RP), and 13 of 29 patients with systemic lupus erythematosus (SLE). Serum V H PAM-V k 16F4-like antibodies were found in 24 of 34 patients with SSc, but not in healthy controls, patients with primary RP, or patients with SLE. Peptides composing the V H PAM-V k 16F4 epitope inhibited PDGFRa signaling triggered by serum IgG from SSc patients.Conclusion. Agonistic anti-PDGFRa autoantibodies are enriched in SSc sera and recognize specific conformational epitopes that can be used to discriminate agonistic from nonagonistic antibodies and block PDGFRa signaling in patients with SSc.

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Functional Importance of Platelet-derived Growth Factor (PDGF) Receptor Extracellular Immunoglobulin-like Domains

Cited by 53 publications

References 37 publications

Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts

Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts

A Novel Myocyte-specific Gene MidoriPromotes the Differentiation of P19CL6 Cells into Cardiomyocytes

Epitope Specificity Determines Pathogenicity and Detectability of Anti–Platelet‐Derived Growth Factor Receptor α Autoantibodies in Systemic Sclerosis

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