Structural Basis for Cytokine Hormone-Receptor Recognition and Receptor Activation

Kossiakoff, A.A.; Vos, Abraham M. de

doi:10.1016/s0065-3233(08)60433-7

Cited by 55 publications

(22 citation statements)

References 99 publications

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“…The generation of signals through receptor dimerization is a general theme. Among the tyrosine kinase receptors the mechanisms of generating the dimer vary from the use of bivalent ligands for growth hormone and erythropoietin (Kossiakoff and de Vos, 1998;Jiang and Hunter, 1999), to dimeric ligands for PDGF and VEGF (Wiesmann et al, 1997), to complexes in which both receptor and ligand mediated the dimer binding as for FGF (Plotnikov et al, 2000). The other large class of transmembrane receptors for soluble ligands are the 7-transmembrane family.…”

Section: Introductionmentioning

confidence: 99%

A Novel Mode for Integrin-mediated Signaling: Tethering Is Required for Phosphorylation of FAK Y397

Shi

Boettiger

2003

MBoC

133

113

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The common model for integrin mediated signaling is based on integrin clustering and the potential for that clustering to recruit signaling molecules including FAK and src. The clustering model for transmembrane signaling originated with the analysis of the EGF receptor signaling and remains the predominant model. The roles for substrate-bound ligand and ligand occupancy in integrin-mediated signaling are less clear. A kinetic model was established using HT1080 cells in which there was a linear relationship between the strength of adhesion, the proportion of ␣5␤1 integrin that could be chemically cross-linked, and the number of receptor-ligand bonds. This graded signal produced a similarly graded response measured by the level of specific phosphorylation of FAK Y397. FAK Y397 phosphorylation could also be induced by antibody bound to the substrate. In contrast, clustering of ␣5␤1 on suspended cells with either antibody to ␤1 or by clustering of soluble ligand bound to ␣5␤1 induced the phosphorylation of FAK Y861 but not Y397. There were no differences in signaling when activating antibodies were compared with blocking antibodies, presence or absence of ligand. Only tethering of ␣5␤1 to the substrate was required for induction of FAK Y397 phosphorylation. INTRODUCTIONThere are several classes of transmembrane receptors that are involved in the transmission of signals from the extracellular space across the plasma membrane. It is a logical requirement of these systems that ligand binding to the extracellular domain results in a change in the cytoplasmic domain. How the signal is transferred from the extracellular domain is basic to the generation of the intracellular downstream signals. Allosteric proteins have been described in which the occupation of a binding site on one side of the protein can result in a conformational change that affects other binding sites. The interposition of a lipid bilayer between the receiving and effector domains of the transmembrane receptors poses limitations in the application of the allosteric model. Although a few of the receptor tyrosine kinase receptor systems have been analyzed in detail, the mechanism for transmembrane signal transduction by other receptor classes is less well understood.The EGF receptor is the best understood model. Receptor dimerization is initiated by the binding of EGF to extracellular domain 1 altering the conformation of the extracellular domain to generate a dimerization of receptors mediated through domain 2. This dimerization brings the cytoplasmic domains of two EGF receptors into proximity and allows the cross-phosphorylation of cytoplasmic domains by the encoded tyrosine kinase (Schlessinger, 2000). The generation of signals through receptor dimerization is a general theme. Among the tyrosine kinase receptors the mechanisms of generating the dimer vary from the use of bivalent ligands for growth hormone and erythropoietin (Kossiakoff and de Vos, 1998;Jiang and Hunter, 1999), to dimeric ligands for PDGF and VEGF (Wiesmann et al., 1997), to complexe...

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Section: Introductionmentioning

confidence: 99%

A Novel Mode for Integrin-mediated Signaling: Tethering Is Required for Phosphorylation of FAK Y397

Shi

Boettiger

2003

MBoC

133

113

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“…These studies and those of related cytokine systems have been instrumental in defining structural similarities within the family that are deterministic for hormone action and regulation (6-12). The structure-based mechanisms by which these systems activate are similar (3,5,9,13). However, although these mechanisms are conceptually simple (hormone-induced receptor aggregation), it is becoming more appreciated that the molecular strategies that are used by each particular system are complex and hardly predictable (4,6,7,14).…”

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confidence: 99%

“…A hallmark of the GH-induced biological activity is a receptor aggregation process involving a receptor homodimerization through a mechanism that requires the two receptor extracellular domains (ECDs) to bind to the hormone in a highly regulated sequential order (13). The sequential order of binding is a consequence of the difference in binding affinities of the hormone's two spatially separated receptor binding sites.…”

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confidence: 99%

The high- and low-affinity receptor binding sites of growth hormone are allosterically coupled

Walsh

Sylvester

Kossiakoff

2004

Proc. Natl. Acad. Sci. U.S.A.

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Growth hormone regulates its biological properties via a sequential hormone-induced receptor homodimerization mechanism. Using a mutagenesis-scanning analysis of 81 single and 32 pairwise double mutations, we show that the hormone's two spatially distal receptor binding sites (Site1 and Site2) are allosterically coupled. These allosteric effects are focused among a relatively few residues centered around the interaction between Asp-116 of the hormone and Trp-169 of the receptor in Site2. A rearrangement of this interaction triggered by mutations in Site1 produces both a major conformation and energetic reorganization of Site2, surprisingly without a reduction in overall binding affinity. Additionally, the data suggest a change in the conformational dynamics of several groups in Site2 that appear to be important in defining the Site2 interaction. Changes in binding energy of the affected Site2 residues usually range in magnitude from 3-to 60-fold, but in one case are as large as 10 4 .W ithin the cytokine super family, the growth hormone (GH)͞prolactin family of hormones and receptors is arguably the most extensively characterized system focused on establishing the structure-function basis for protein-protein interactions (1-5). These studies and those of related cytokine systems have been instrumental in defining structural similarities within the family that are deterministic for hormone action and regulation (6-12). The structure-based mechanisms by which these systems activate are similar (3,5,9,13). However, although these mechanisms are conceptually simple (hormone-induced receptor aggregation), it is becoming more appreciated that the molecular strategies that are used by each particular system are complex and hardly predictable (4,6,7,14).A hallmark of the GH-induced biological activity is a receptor aggregation process involving a receptor homodimerization through a mechanism that requires the two receptor extracellular domains (ECDs) to bind to the hormone in a highly regulated sequential order (13). The sequential order of binding is a consequence of the difference in binding affinities of the hormone's two spatially separated receptor binding sites. A highaffinity site, Site1, is always occupied first by the receptor ECD (R1) to form a stable 1:1 hormone-receptor intermediate complex [human GH (hGH)͞R1] (15). This 1:1 complex provides the structural platform for binding the second receptor ECD (R2) through two spatially distinct subsites, which are independently weak but together produce a tight R2 association. One subsite is located on the opposite face of the hormone to Site1 and is referred to as Site2 (Fig. 1). The second subsite, the so-called stem-stem contact, is formed by an extensive set of interactions between the C-terminal portions of the ECDs of the two receptor ECDs. Although it is clear that the two receptor ECDs are structurally integrated through this stem-stem contact, there is no direct evidence to suggest that the Site1 and Site2 binding sites on the hormone have any structural lin...

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“…Receptor dimerization is further stabilized by additional receptorreceptor interactions [3][4]. In the case of homodimeric growth factors, as PDGF, the receptor becomes dimerised by direct interaction with the ligand.…”

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confidence: 99%

Receptor Tyrosine Kinases as Target for Anti-Cancer Therapy

Brunelleschi

Penengo²,

Santoro³

et al. 2002

CPD

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Abstract:Receptor tyrosine kinases (RTKs) are cell surface transmembrane proteins responsible for intracellular signal transduction. They are expressed in several cell types and, after activation by growth factor binding, trigger a series of intracellular pathways, leading to a wide variety of cell responses (e.g., differentiation, proliferation, migration and invasion, angiogenesis, survival). Over-expression and/or structural alteration of RTKs family members are often associated to human cancers and tumor cells are known to use RTK transduction pathways to achieve tumor growth, angiogenesis and metastasis. Therefore, RTKs represent pivotal target in approaches of cancer therapy. A number of small molecules acting as RTK inhibitors have been synthesized by pharmaceutical companies and are under clinical trials, are being analyzed in animal models or have been successfully marketed. Liganddependent downregulation of RTKs is a critical step for modulating their activity and the adaptor Cbl has been indicated as the key protein involved in negative regulation of RTKs, such as EGF and HGF receptors. These data suggest novel potential pharmacological targets for the treatment of human malignancies associated to oncogenic activation of RTKs.Keywords: Growth Factor Receptor -Tyrosine kinase -Tyrosine kinase Inhibitor -Signal transduction -CancerDownregulation RECEPTOR TYROSINE KINASES (RTKS)Growth factors are extracellular signals that regulate cell proliferation and differentiation. The vast majority of them, such as Platelet-Derived Growth Factor (PDGF), Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), Vascular Endothelial Growth Factor (VEGF), Hepatocyte Growth Factor (HGF) and others, bind to receptors with tyrosine kinase activity (RTKs), which have been often involved in human cancers. RTKs consist of an extracellular ligand binding domain, usually glycosylated, connected to the cytoplasmic domain by a single transmembrane helix. The intracellular domain contains a conserved protein tyrosine kinase core and additional regulatory sequences that undergo phosphorylation. The extracellular domain displays different structural elements, such as one or more copies of Immunoglobulin-like domains, fibronectin type III-like repeats, EGF-like domains, cysteine-rich regions and other features [1].Based on their structural extracellular characteristics, RTKs can be classified into approximately twenty families. Some examples of receptors altered in human cancer are listed here: family I, EGF receptor and its homologs, with two cysteine-rich domains; family III, PDGF receptors, with five Immunoglobulin-like domains; family IV, FGF receptors, with three Immunoglobulin-like domains; family *Address corresponding to this author at the University of Piemonte Orientale "A.Avogadro", Department of Medical Sciences, via Solaroli, 17, 28100 Novara, Italy; Email: giovanni.gaudino@unipmn.it V, VEGF receptors with seven immunoglobulin domains; family VI, the HGF receptor and its homologs, that have a heterodimeric struct...

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Structural Basis for Cytokine Hormone-Receptor Recognition and Receptor Activation

Cited by 55 publications

References 99 publications

A Novel Mode for Integrin-mediated Signaling: Tethering Is Required for Phosphorylation of FAK Y397

A Novel Mode for Integrin-mediated Signaling: Tethering Is Required for Phosphorylation of FAK Y397

The high- and low-affinity receptor binding sites of growth hormone are allosterically coupled

Receptor Tyrosine Kinases as Target for Anti-Cancer Therapy

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