Dimerization of B-type Platelet-derived Growth Factor Receptors Occurs After Ligand Binding and Is Closely Associated with Receptor Kinase Activation

Heldin, Carl‐Henrik; Ernlund, Agneta; Rorsman, Charlotte; Rönnstrand, Lars

doi:10.1016/s0021-9258(18)81879-8

Cited by 339 publications

(34 citation statements)

References 36 publications

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“…The experimental evidence underlying the current model of ligand-induced TrkA receptor dimerization is derived primarily from chemical cross-linking studies (Jing et al, 1992;Meakin and Shooter, 1991;Schlessinger and Ullrich, 1992). Similar cross-linking studies of the platelet derived growth factor receptor ␤ (PDGF-␤) and the epidermal growth factor receptor (EGFR) also suggested that these receptors exist in the plasma membrane as monomers that dimerize upon addition of ligand (Cochet et al, 1988;Heldin et al, 1989;Inui et al, 1993). However, the use of new biophysical methods such as fluorescence resonance energy transfer (FRET) and image correlation spectroscopy (ICS) have challenged this model.…”

Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor Signals via Preexisting TrkA Receptor Oligomers

Mischel

Umbach

Eskandari

et al. 2002

Biophysical Journal

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Nerve growth factor (NGF) promotes neuronal survival and differentiation by activating TrkA receptors. Similar to other receptor tyrosine kinases, ligand-induced dimerization is thought to be required for TrkA receptor activation. To study this process, we expressed TrkA receptors in Xenopus laevis oocytes and analyzed their response to NGF by using a combination of functional, biochemical, and structural approaches. TrkA receptor protein was detected in the membrane fraction of oocytes injected with TrkA receptor cRNA, but not in uninjected or mock-injected oocytes. Application of NGF to TrkA receptor-expressing oocytes promoted tyrosine phosphorylation and activated an oscillating transmembrane inward current, indicating that the TrkA receptors were functional. Freeze-fracture electron microscopic analysis demonstrated novel transmembrane particles in the P-face (protoplasmic face) of oocytes injected with TrkA cRNA, but not in uninjected or mock injected oocytes. Incubating TrkA cRNA-injected oocytes with the transcriptional inhibitor actinomycin D did not prevent the appearance of these P-face particles or electrophysiological responses to NGF, demonstrating that they did not arise from de novo transcription of an endogenous Xenopus oocyte gene. The appearance of these particles in the plasma membrane correlated with responsiveness to NGF as detected by electrophysiological analysis and receptor phosphorylation, indicating that these novel P-face particles were TrkA receptors. The dimensions of these particles (8.6 x 10 nm) were too large to be accounted for by TrkA monomers, suggesting the formation of TrkA receptor oligomers. Application of NGF did not lead to a discernible change in the size or shape of these TrkA receptor particles during an active response. These results indicate that in Xenopus oocytes, NGF activates signaling via pre-formed TrkA receptor oligomers.

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Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor Signals via Preexisting TrkA Receptor Oligomers

Mischel

Umbach

Eskandari

et al. 2002

Biophysical Journal

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“…Aggregation of cell surface receptors is a common mechanism involved in signal transduction across a cell membrane (Metzger, 1992). This mechanism is used, for example, by receptors that are intrinsic protein tyrosine kinases (Pazin and Williams, 1992;Fry et al, 1993), such as the epidermal growth factor receptor (Schreiber et al, 1982) and the platelet derived growth factor receptor (Heldin et al, 1989), and by multichain immune recognition receptors (Keegan and Paul, 1992), such as the high affinity receptor for IgE (Fc⑀RI) (Holowka and Baird, 1996) and the B-cell receptor (Kaye et al, 1983;Kaye and Janeway, 1984;Cambier and Ransom, 1987). For many of these receptors, early steps in the initiation of a signal are similar: multivalent interactions with a ligand lead to the aggregation of receptors and enhanced phosphorylation of tyrosines, which can be recognized by cytoplasmic regulatory molecules.…”

Section: Introductionmentioning

confidence: 99%

Quantifying Aggregation of IgE-FcϵRI by Multivalent Antigen

Hlavacek

Perelson

Sulzer

et al. 1999

Biophysical Journal

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Aggregation of cell surface receptors by multivalent ligand can trigger a variety of cellular responses. A well-studied receptor that responds to aggregation is the high affinity receptor for IgE (FcepsilonRI), which is responsible for initiating allergic reactions. To quantify antigen-induced aggregation of IgE-FcepsilonRI complexes, we have developed a method based on multiparameter flow cytometry to monitor both occupancy of surface IgE combining sites and association of antigen with the cell surface. The number of bound IgE combining sites in excess of the number of bound antigens, the number of bridges between receptors, provides a quantitative measure of IgE-FcepsilonRI aggregation. We demonstrate our method by using it to study the equilibrium binding of a haptenated fluorescent protein, 2,4-dinitrophenol-coupled B-phycoerythrin (DNP25-PE), to fluorescein isothiocyanate-labeled anti-DNP IgE on the surface of rat basophilic leukemia cells. The results, which we analyze with the aid of a mathematical model, indicate how IgE-FcepsilonRI aggregation depends on the total concentrations of DNP25-PE and surface IgE. As expected, we find that maximal aggregation occurs at an optimal antigen concentration. We also find that aggregation varies qualitatively with the total concentration of surface IgE as predicted by an earlier theoretical analysis.

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“…Homodimeric (PDGF-AA, PDGF-BB) as well as heterodimeric (PDGF-AB) isoforms exert their effects on target cells by binding with different speci®cities to two structurally related protein tyrosine kinase receptors, denoted the a-and breceptors (Hart et al, 1988;Heldin et al, 1988). PDGF-AA induces aa receptor dimers, PDGF-AB aa or ab receptor dimers, and PDGF-BB all three possible combinations of receptor dimers (Bishayee et al, 1989;Heldin et al, 1989;Seifert et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Mitogenic Activity of Dermatofibrosarcoma Protuberans is Mediated via an Extracellular Signal Related Kinase Dependent Pathway

Ihn

Tamaki

2002

Journal of Investigative Dermatology

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Dermatofibrosarcoma protuberans is a malignant mesenchymal tumor originating in the dermis. Although it is locally aggressive and recurs unless completely excised, it only rarely metastasizes. In this study, we investigated the mechanisms of increased proliferation of dermatofibrosarcoma protuberans cells. The cells showed increased DNA synthesis in serum-free medium, which was demonstrated by the incorporation of [3H]-thymidine. Increased DNA synthesis of dermatofibrosarcoma protuberans cells was abolished by genistein, a tyrosine kinase inhibitor, or by PD98059, a specific extracellular signal related kinase pathway inhibitor, but not by calphostin C, a protein kinase C inhibitor. Immunoblotting analysis of dermatofibrosarcoma protuberans cells using a specific antibody against phosphorylated extracellular signal related kinase (Thr202/Tyr204) showed that extracellular signal related kinase was expressed as constitutively phosphorylated molecules in dermatofibrosarcoma protuberans cells. Immunofluorescence analysis showed that the kinase was constitutively located in the nucleus of the cells. Furthermore, transfection of the dominant negative mutant extracellular signal related kinase into dermatofibrosarcoma protuberans cells abolished the increased mitogenic activity of the cells. These results suggest that an extracellular signal related kinase dependent pathway is implicated in the increased mitogenic activity of dermatofibrosarcoma protuberans cells.

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Dimerization of B-type Platelet-derived Growth Factor Receptors Occurs After Ligand Binding and Is Closely Associated with Receptor Kinase Activation

Cited by 339 publications

References 36 publications

Nerve Growth Factor Signals via Preexisting TrkA Receptor Oligomers

Nerve Growth Factor Signals via Preexisting TrkA Receptor Oligomers

Quantifying Aggregation of IgE-FcϵRI by Multivalent Antigen

Mitogenic Activity of Dermatofibrosarcoma Protuberans is Mediated via an Extracellular Signal Related Kinase Dependent Pathway

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