Mapping and Immunomodulation of the Cell Surface Protein Architecture with Therapeutic Implications: Fluorescence Is a Key Tool of Solution

Nagy, Péter; Balogh, Andrea; Szöllősi, János; Matkó, János

doi:10.1007/978-1-4419-9672-5_8

Cited by 4 publications

(5 citation statements)

References 134 publications

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“… The dipole potential may only exert a permissive effect on clustering which is not strong enough for altering the weak and transient constitutive dimers and oligomers. It has been suggested that constitutive dimers or oligomers are generated by corralling or confinement by the cytoskeleton 10 , while actively signaling receptor clusters are held together by protein-protein interactions 41 42 . Since it is unlikely that the membrane dipole potential affects corralling and confinement, it only exerts effects on ligand-induced clusters.…”

Section: Discussionmentioning

confidence: 99%

The Dipole Potential Modifies the Clustering and Ligand Binding Affinity of ErbB Proteins and Their Signaling Efficiency

Kovács

Batta

Hajdu

et al. 2016

Sci Rep

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Although activation of the ErbB family of receptor tyrosine kinases (ErbB1-4) is driven by oligomerization mediated by intermolecular interactions between the extracellular, the kinase and the transmembrane domains, the transmembrane domain has been largely neglected in this regard. The largest contributor to the intramembrane electric field, the dipole potential, alters the conformation of transmembrane peptides, but its effect on ErbB proteins is unknown. Here, we show by Förster resonance energy transfer (FRET) and number and brightness (N&B) experiments that the epidermal growth factor (EGF)-induced increase in the homoassociation of ErbB1 and ErbB2 and their heteroassociation are augmented by increasing the dipole potential. These effects were even more pronounced for ErbB2 harboring an activating Val → Glu mutation in the transmembrane domain (NeuT). The signaling capacity of ErbB1 and ErbB2 was also correlated with the dipole potential. Since the dipole potential decreased the affinity of EGF to ErbB1, the augmented growth factor-induced effects at an elevated dipole potential were actually induced at lower receptor occupancy. We conclude that the dipole potential plays a permissive role in the clustering of ErbB receptors and that the effects of lipid rafts on ligand binding and receptor signaling can be partially attributed to the dipole potential.

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Section: Discussionmentioning

confidence: 99%

The Dipole Potential Modifies the Clustering and Ligand Binding Affinity of ErbB Proteins and Their Signaling Efficiency

Kovács

Batta

Hajdu

et al. 2016

Sci Rep

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“…Detailed biophysical studies revealed the existence of three hierarchical layers of receptor clusters: 1) dimerization driven by protein-protein interactions; 2) oligomerization generated by preferential distribution in lipid microdomains (referred to as large-scale clusters in the previous paragraph); and 3) clusters with a diameter of ∼100 nm or more visible even in light microscopy ( 22 , 23 ). Biophysical techniques show different potentials to detect these clusters, depending on their size, stability, and mobility ( 22 , 24 ).…”

Section: Introductionmentioning

confidence: 99%

Homo- and Heteroassociations Drive Activation of ErbB3

Váradi

Schneider

Sevcsik

et al. 2019

Biophysical Journal

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Dimerization or the formation of higher-order oligomers is required for the activation of ErbB receptor tyrosine kinases. The heregulin (HRG) receptor, ErbB3, must heterodimerize with other members of the family, preferentially ErbB2, to form a functional signal transducing complex. Here, we applied single molecule imaging capable of detecting long-lived and mobile associations to measure their stoichiometry and mobility and analyzed data from experiments globally, taking the different lateral mobility of monomeric and dimeric molecular species into account. Although ErbB3 was largely monomeric in the absence of stimulation and ErbB2 co-expression, a small fraction was present as constitutive homodimers exhibiting a ∼40% lower mobility than monomers. HRG stimulation increased the homodimeric fraction of ErbB3 significantly and reduced the mobility of homodimers fourfold compared to constitutive homodimers. Expression of ErbB2 elevated the homodimeric fraction of ErbB3 even in unstimulated cells and induced a ∼2-fold reduction in the lateral mobility of ErbB3 homodimers. The mobility of ErbB2 was significantly lower than that of ErbB3, and HRG induced a less pronounced decrease in the diffusion coefficient of all ErbB2 molecules and ErbB3/ErbB2 heterodimers than in the mobility of ErbB3. The slower diffusion of ErbB2 compared to ErbB3 was abolished by depolymerizing actin filaments, whereas ErbB2 expression induced a substantial rearrangement of microfilaments, implying a bidirectional interaction between ErbB2 and actin. HRG stimulation of cells co-expressing ErbB3 and ErbB2 led to the formation of ErbB3 homodimers and ErbB3/ErbB2 heterodimers in a competitive fashion. Although pertuzumab, an antibody binding to the dimerization arm of ErbB2, completely abolished the formation of constitutive and HRG-induced ErbB3/ErbB2 heterodimers, it only slightly blocked ErbB3 homodimerization. The results imply that a dynamic equilibrium exists between constitutive and ligand-induced homo- and heterodimers capable of shaping transmembrane signaling.

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“…Besides these two hierarchical levels of clustering, both ErbB1 and ErbB2 have been shown to form a third level of associations with characteristic diameters in the hundreds of nanometer range, which are beyond the scope of the current review [ 104 , 105 ]. This three-level domain organization seems to be a general feature of membrane proteins [ 106 , 107 ]. While there are some inconsistencies between the potential interpretation of results discussed in the previous paragraphs, a plausible model is presented in Figure 2 .…”

Section: Dimerization-induced Activation Of Receptor Tyrosine Kinasesmentioning

confidence: 99%

It Takes More than Two to Tango: Complex, Hierarchal, and Membrane-Modulated Interactions in the Regulation of Receptor Tyrosine Kinases

Kovács

Zakany

Nagy

2022

Cancers

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The search for an understanding of how cell fate and motility are regulated is not a purely scientific undertaking, but it can also lead to rationally designed therapies against cancer. The discovery of tyrosine kinases about half a century ago, the subsequent characterization of certain transmembrane receptors harboring tyrosine kinase activity, and their connection to the development of human cancer ushered in a new age with the hope of finding a treatment for malignant diseases in the foreseeable future. However, painstaking efforts were required to uncover the principles of how these receptors with intrinsic tyrosine kinase activity are regulated. Developments in molecular and structural biology and biophysical approaches paved the way towards better understanding of these pathways. Discoveries in the past twenty years first resulted in the formulation of textbook dogmas, such as dimerization-driven receptor association, which were followed by fine-tuning the model. In this review, the role of molecular interactions taking place during the activation of receptor tyrosine kinases, with special attention to the epidermal growth factor receptor family, will be discussed. The fact that these receptors are anchored in the membrane provides ample opportunities for modulatory lipid–protein interactions that will be considered in detail in the second part of the manuscript. Although qualitative and quantitative alterations in lipids in cancer are not sufficient in their own right to drive the malignant transformation, they both contribute to tumor formation and also provide ways to treat cancer. The review will be concluded with a summary of these medical aspects of lipid–protein interactions.

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Mapping and Immunomodulation of the Cell Surface Protein Architecture with Therapeutic Implications: Fluorescence Is a Key Tool of Solution

Cited by 4 publications

References 134 publications

The Dipole Potential Modifies the Clustering and Ligand Binding Affinity of ErbB Proteins and Their Signaling Efficiency

The Dipole Potential Modifies the Clustering and Ligand Binding Affinity of ErbB Proteins and Their Signaling Efficiency

Homo- and Heteroassociations Drive Activation of ErbB3

It Takes More than Two to Tango: Complex, Hierarchal, and Membrane-Modulated Interactions in the Regulation of Receptor Tyrosine Kinases

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