Interaction of Epidermal Growth Factor with Its Receptor

Campion, Stephen R.; Niyogi, Salil K.

doi:10.1016/s0079-6603(08)60055-0

Cited by 25 publications

(25 citation statements)

References 85 publications

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“…Furthermore, all T1E variants selected for ErbB-3 binding maintained their ability to bind to ErbB-1 expressed on 32D cells and ErbB-1-IgG ectodomains, indicating that the requirements in the C-terminal tail for ErbB-1 and ErbB-3 interaction may partly overlap. 2 This observation is remarkable since the majority of selected clones lacked a Leu or Ile at position 49 in T1E (Leu-47 in EGF), which is strictly conserved among ErbB-1 ligands and known to be highly sensitive to site-directed mutagenesis (13,14).…”

Section: The Linear C-terminal Region Of T1e Influences the Erbb-2/ermentioning

confidence: 99%

“…Structural and mutational analyses have shown that residues in the A-loop, C-loop, and C-terminal linear region of EGF and TGF-␣ primarily bind to domain III of ErbB-1 followed by an interaction of residues in their B-loop with domain I of the receptor (1,2,(13)(14)(15)(16). By contrast, NRG-1␤ has been shown to bind with high affinity to a proteolytic fragment of ErbB-3 containing only domain I (17).…”

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confidence: 99%

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Selective Formation of ErbB-2/ErbB-3 Heterodimers Depends on the ErbB-3 Affinity of Epidermal Growth Factor-like Ligands

Stortelers

Woning

Jacobs-Oomen

et al. 2003

Journal of Biological Chemistry

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EGF-like growth factors activate their ErbB receptorsby promoting receptor-mediated homodimerization or, alternatively, by the formation of heterodimers with the orphan ErbB-2 through an as yet unknown mechanism. To investigate the selectivity in dimer formation by ligands, we have applied the phage display approach to obtain ligands with modified C-terminal residues that discriminate between ErbB-2 and ErbB-3 as dimerization partners. We used the epidermal growth factor/ transforming growth factor ␣ chimera T1E as the template molecule because it binds to ErbB-3 homodimers with low affinity and to ErbB-2/ErbB-3 heterodimers with high affinity. Many phage variants were selected with enhanced binding affinity for ErbB-3 homodimers, indicating that C-terminal residues contribute to the interaction with ErbB-3. These variants were also potent ligands for ErbB-2/ErbB-3 heterodimers despite negative selection for such heterodimers. In contrast, phage variants positively selected for binding to ErbB-2/ErbB-3 heterodimers but negatively selected for binding to ErbB-3 homodimers can be considered as "second best" ErbB-3 binders, which require ErbB-2 heterodimerization for stable complex formation. Our findings imply that epidermal growth factor-like ligands bind ErbB-3 through a multi-domain interaction involving at least both linear endings of the ligand. Apparently the ErbB-3 affinity of a ligand determines whether it can form only ErbB-2/ErbB-3 complexes or also ErbB-3 homodimers. Because no separate binding domain for ErbB-2 could be identified, our data support a model in which ErbB heterodimerization occurs through a receptor-mediated mechanism and not through bivalent ligands.The recent determination of the crystal structure of the extracellular domain of ErbB-1 in complex with its ligands epidermal growth factor (EGF) 1 or transforming growth factor ␣ (TGF-␣) has provided evidence for the formation of homodimeric ErbB-1 complexes through a receptor-mediated dimerization mechanism (1, 2). Ligand binding to both domains I and III of the extracellular domain of the receptor involves the transition of ErbB-1 from a "closed" to an "open" state, which then permits dimerization with another liganded ErbB-1 through interaction of domain II residues within these receptors. Most likely this mechanism can serve as a paradigm for homodimerization of other liganded ErbB receptors, such as ErbB-3 and ErbB-4. However, it is well established that EGFlike growth factors preferentially signal through heterodimers of their cognate receptor with the orphan ErbB-2. The mechanism by which EGF-like growth factors bind their receptors in heterodimeric receptor complexes remains an open question.Dimerization of ligand-bound receptor tyrosine kinases is a mechanism that is thought to activate the intrinsic kinase domain followed by transphosphorylation and subsequent docking of cellular signal transducing proteins. As a consequence, ligand binding serves as a potential site for regulation of cell proliferation in diseases where ErbB rece...

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Section: The Linear C-terminal Region Of T1e Influences the Erbb-2/ermentioning

confidence: 99%

mentioning

confidence: 99%

Selective Formation of ErbB-2/ErbB-3 Heterodimers Depends on the ErbB-3 Affinity of Epidermal Growth Factor-like Ligands

Stortelers

Woning

Jacobs-Oomen

et al. 2003

Journal of Biological Chemistry

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“…A series of hydrophobic and positively charged aminoacids in loops I and III of one monomer and loop II of the head-to tail linked second monomer represent the critical residues for PDGF binding to its receptor [50]. As far as VEGF is concerned, its receptor binding regions are composed of hydrophobic and negatively charged regions [61], whereas EGF has a completely different structure to PDGF and VEGF [62]. Therefore, given the variance of the receptor binding domains of these three growth factors, this approach is suitable to design molecules able to bind selectively to a target growth factor.…”

Section: Tyrosine Kinase Inhibitors Of the Pdgf Family (Pdgf Receptormentioning

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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“…Indeed, although the function of this B-loop remains uncertain, many studies have implicated it in EGF binding and activation of the receptor (11, 49 -51). The C-loop of EGF domains, between cysteines 5 and 6, is also critical for the function of EGF-like ligands (10). In Argos, the C-loop is also atypical.…”

Section: N-and C-terminal Truncations Ofmentioning

confidence: 99%

In Vivo Analysis of Argos Structure-Function

Howes

Wasserman

Freeman

1998

Journal of Biological Chemistry

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The Drosophila Argos protein is the only known extracellular inhibitor of the epidermal growth factor receptor (EGFR). It is structurally related to the activating ligands, in that it is a secreted protein with a single epidermal growth factor (EGF) domain. To understand the mechanism of Argos inhibition, we have investigated which regions of the protein are essential. A series of deletions were made and tested in vivo; furthermore, by analyzing chimeric proteins between Argos and the activating ligand, Spitz (a transforming growth factor-␣-like factor), we have examined what makes one inhibitory and the other activating. Our results reveal that Argos has structural requirements that differ from all known EGFR activating ligands; domains flanking the EGF domain are essential for its function. We have also defined the important regions of the atypical Argos EGF domain. The extended B-loop is necessary, whereas the C-loop can be replaced with the equivalent Spitz region without substantially affecting Argos function. Comparison of the argos genes from Drosophila melanogaster and the housefly, Musca domestica, supports our structure-function analysis. These studies are a prerequisite for understanding how Argos inhibits the Drosophila EGFR and provide a basis for designing mammalian EGFR inhibitors. The epidermal growth factor receptor (EGFR)1 controls many aspects of animal growth, development, and cell proliferation (1). How these different roles are coordinated and their relative importance in normal development is not yet well understood, but it is clear that overactivation of the receptor in mammals is implicated in many forms of cancer (2-5). This overactivation can be caused by amplification of the receptor gene, by activating mutations in the receptor, or frequently by overexpression of activating ligands, which causes inappropriate autocrine signaling. The EGFR is a tyrosine kinase; it has an extracellular ligand binding domain and an intracellular kinase domain. As with other receptor tyrosine kinases, it forms dimers upon activation, and these then transphosphorylate each other, causing the activation of downstream signal transduction pathways (6). There are four members of the EGFR family in mammals (ErbB1-ErbB4), and they act in a complex set of overlapping functions, both as homo-and heterodimers (7). They are activated by several classes of ligand, including EGF itself, transforming growth factor-␣ (TGF␣), neuregulins, and others. The motif responsible for receptor activation in all known ligands is an EGF domain, comprising six characteristically spaced cysteines and a few other essential amino acids (8). Antagonists of the EGFR might have therapeutic potential, and much effort has been made to understand ligand binding and activation, to help design such inhibitors (9 -14). Although several important regions have been identified, effective antagonists have remained elusive because of the apparent inability to uncouple receptor binding and activation; all mutants that still bind efficiently are acti...

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Interaction of Epidermal Growth Factor with Its Receptor

Cited by 25 publications

References 85 publications

Selective Formation of ErbB-2/ErbB-3 Heterodimers Depends on the ErbB-3 Affinity of Epidermal Growth Factor-like Ligands

Selective Formation of ErbB-2/ErbB-3 Heterodimers Depends on the ErbB-3 Affinity of Epidermal Growth Factor-like Ligands

Receptor Tyrosine Kinases as Target for Anti-Cancer Therapy

In Vivo Analysis of Argos Structure-Function

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