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HER2 therapy. HER2 (ERBB2): functional diversity from structurally conserved building blocks.

Landgraf R - Breast Cancer Res. (2007)

Bottom Line: EGFR-type receptor tyrosine kinases achieve a broad spectrum of cellular responses by utilizing a set of structurally conserved building blocks.Based on available crystal structures and biochemical information, significant new insights have emerged into modes of receptor control, its deregulation in cancer, and the nuances that differentiate the four human receptors.This review gives an overview of current models of the control of receptor activity with a special emphasis on HER2 and HER3.

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Affiliation: University of California Los Angeles, Department of Medicine, Hematology-Oncology and Biological Chemistry, Molecular Biology Institute, Los Angeles, California 90095-1678, USA. rlandgraf@mednet.ucla.edu

ABSTRACT
EGFR-type receptor tyrosine kinases achieve a broad spectrum of cellular responses by utilizing a set of structurally conserved building blocks. Based on available crystal structures and biochemical information, significant new insights have emerged into modes of receptor control, its deregulation in cancer, and the nuances that differentiate the four human receptors. This review gives an overview of current models of the control of receptor activity with a special emphasis on HER2 and HER3.

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Schematic representation of domains, conformations, and sites of interaction in HER2 and HER3. (a) Domain structure of monomeric HER2, indicating ECDs I to IV with the primary and secondary dimerization loop in the fifth and sixth module of domain II, a single transmembrane span, the cytoplasmic juxtamembrane segment (* indicates the site of PKC-mediated threonine phosphorylation), the amino- and carboxyl-terminal lobe of the kinase domain, and the carboxyl-terminal tail carrying most adapter binding sites. The sites targeted by Herceptin (Herc.), calmodulin (CaM), and Hsp90 are indicated with arrows. (b) Model of HER2-HER3 heterodimer with bound ligand. NRG indicates the EGF-like domain of neuregulin, bound between domains I and III, and Ig indicates the location of the immunoglobulin-like amino-terminal domain of neuregulins. The receptor dimer is stabilized by reciprocal interactions between domains II of both receptors. The physical separation of domains IV in the diagram does not necessarily indicate physical distance but is meant to emphasize that based on experimental data, and in contrast to transmembrane span packing, domain IV interactions do not contribute significantly to dimer stabilization. The exact nature of interactions by both components (boxed with dashed lines) is not clear at this point. The indicated interactions of the cytoplasmic kinase domains summarize the recently proposed mode of allosteric activation based on EGFR structures [38]. (c) HER3 in the closed/locked conformation, stabilized by an intramolecular tether involving the primary dimerization loop in domain II and its structural equivalent in domain IV. ECD, extracellular domain; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor; PKC, protein kinase C.
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Figure 1: Schematic representation of domains, conformations, and sites of interaction in HER2 and HER3. (a) Domain structure of monomeric HER2, indicating ECDs I to IV with the primary and secondary dimerization loop in the fifth and sixth module of domain II, a single transmembrane span, the cytoplasmic juxtamembrane segment (* indicates the site of PKC-mediated threonine phosphorylation), the amino- and carboxyl-terminal lobe of the kinase domain, and the carboxyl-terminal tail carrying most adapter binding sites. The sites targeted by Herceptin (Herc.), calmodulin (CaM), and Hsp90 are indicated with arrows. (b) Model of HER2-HER3 heterodimer with bound ligand. NRG indicates the EGF-like domain of neuregulin, bound between domains I and III, and Ig indicates the location of the immunoglobulin-like amino-terminal domain of neuregulins. The receptor dimer is stabilized by reciprocal interactions between domains II of both receptors. The physical separation of domains IV in the diagram does not necessarily indicate physical distance but is meant to emphasize that based on experimental data, and in contrast to transmembrane span packing, domain IV interactions do not contribute significantly to dimer stabilization. The exact nature of interactions by both components (boxed with dashed lines) is not clear at this point. The indicated interactions of the cytoplasmic kinase domains summarize the recently proposed mode of allosteric activation based on EGFR structures [38]. (c) HER3 in the closed/locked conformation, stabilized by an intramolecular tether involving the primary dimerization loop in domain II and its structural equivalent in domain IV. ECD, extracellular domain; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor; PKC, protein kinase C.

Mentions: All four EGFR-type RTKs share a very conserved structural framework (Figure 1a), which consists of four ECDs, a single transmembrane span, a cytoplasmic juxtamembrane linker region, a tyrosine kinase component, and a carboxyl-terminal tail. This carboxyl-terminal tail is the main substrate of activation-dependent tyrosine phosphorylation and subsequent recruitment of adapter proteins, although tyrosine phosphorylation has also been reported in the kinase domains itself [4,5]. The basic paradigm for activation control centers on ligand-induced homo- and hetero-dimerization of receptors, followed by tyrosine phosphorylation of the cytoplasmic portions of the receptors in trans. Based on confirmed receptor tyrosine phosphorylation sites, a recent microarray-based study determined the ability of such tyrosine phosphorylated-peptides to recruit SH2 or phosphotyrosine-binding domains [4]. This study revealed significant differences between the four RTK family members. Although HER3 exhibited few changes in its recruitment pattern as a function of peptide ('bait') concentration, significant changes occurred for HER2 suggesting that the complement of adapter proteins recruited by activated HER2 would qualitatively vary significantly more as a function of the levels of activated receptors. In addition, a projection for different receptor pairs showed that the HER2/HER3 heterodimer outperforms other RTK combinations in terms of the range of recruited adapters and its ability to carry out efficient recruitment at low to medium concentrations of tyrosine phosphorylated sites. This is consistent with earlier observations that the HER2/HER3 heterodimer represents the most potent mitogenic signaling pair [2].


HER2 therapy. HER2 (ERBB2): functional diversity from structurally conserved building blocks.

Landgraf R - Breast Cancer Res. (2007)

Schematic representation of domains, conformations, and sites of interaction in HER2 and HER3. (a) Domain structure of monomeric HER2, indicating ECDs I to IV with the primary and secondary dimerization loop in the fifth and sixth module of domain II, a single transmembrane span, the cytoplasmic juxtamembrane segment (* indicates the site of PKC-mediated threonine phosphorylation), the amino- and carboxyl-terminal lobe of the kinase domain, and the carboxyl-terminal tail carrying most adapter binding sites. The sites targeted by Herceptin (Herc.), calmodulin (CaM), and Hsp90 are indicated with arrows. (b) Model of HER2-HER3 heterodimer with bound ligand. NRG indicates the EGF-like domain of neuregulin, bound between domains I and III, and Ig indicates the location of the immunoglobulin-like amino-terminal domain of neuregulins. The receptor dimer is stabilized by reciprocal interactions between domains II of both receptors. The physical separation of domains IV in the diagram does not necessarily indicate physical distance but is meant to emphasize that based on experimental data, and in contrast to transmembrane span packing, domain IV interactions do not contribute significantly to dimer stabilization. The exact nature of interactions by both components (boxed with dashed lines) is not clear at this point. The indicated interactions of the cytoplasmic kinase domains summarize the recently proposed mode of allosteric activation based on EGFR structures [38]. (c) HER3 in the closed/locked conformation, stabilized by an intramolecular tether involving the primary dimerization loop in domain II and its structural equivalent in domain IV. ECD, extracellular domain; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor; PKC, protein kinase C.
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Figure 1: Schematic representation of domains, conformations, and sites of interaction in HER2 and HER3. (a) Domain structure of monomeric HER2, indicating ECDs I to IV with the primary and secondary dimerization loop in the fifth and sixth module of domain II, a single transmembrane span, the cytoplasmic juxtamembrane segment (* indicates the site of PKC-mediated threonine phosphorylation), the amino- and carboxyl-terminal lobe of the kinase domain, and the carboxyl-terminal tail carrying most adapter binding sites. The sites targeted by Herceptin (Herc.), calmodulin (CaM), and Hsp90 are indicated with arrows. (b) Model of HER2-HER3 heterodimer with bound ligand. NRG indicates the EGF-like domain of neuregulin, bound between domains I and III, and Ig indicates the location of the immunoglobulin-like amino-terminal domain of neuregulins. The receptor dimer is stabilized by reciprocal interactions between domains II of both receptors. The physical separation of domains IV in the diagram does not necessarily indicate physical distance but is meant to emphasize that based on experimental data, and in contrast to transmembrane span packing, domain IV interactions do not contribute significantly to dimer stabilization. The exact nature of interactions by both components (boxed with dashed lines) is not clear at this point. The indicated interactions of the cytoplasmic kinase domains summarize the recently proposed mode of allosteric activation based on EGFR structures [38]. (c) HER3 in the closed/locked conformation, stabilized by an intramolecular tether involving the primary dimerization loop in domain II and its structural equivalent in domain IV. ECD, extracellular domain; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor; PKC, protein kinase C.
Mentions: All four EGFR-type RTKs share a very conserved structural framework (Figure 1a), which consists of four ECDs, a single transmembrane span, a cytoplasmic juxtamembrane linker region, a tyrosine kinase component, and a carboxyl-terminal tail. This carboxyl-terminal tail is the main substrate of activation-dependent tyrosine phosphorylation and subsequent recruitment of adapter proteins, although tyrosine phosphorylation has also been reported in the kinase domains itself [4,5]. The basic paradigm for activation control centers on ligand-induced homo- and hetero-dimerization of receptors, followed by tyrosine phosphorylation of the cytoplasmic portions of the receptors in trans. Based on confirmed receptor tyrosine phosphorylation sites, a recent microarray-based study determined the ability of such tyrosine phosphorylated-peptides to recruit SH2 or phosphotyrosine-binding domains [4]. This study revealed significant differences between the four RTK family members. Although HER3 exhibited few changes in its recruitment pattern as a function of peptide ('bait') concentration, significant changes occurred for HER2 suggesting that the complement of adapter proteins recruited by activated HER2 would qualitatively vary significantly more as a function of the levels of activated receptors. In addition, a projection for different receptor pairs showed that the HER2/HER3 heterodimer outperforms other RTK combinations in terms of the range of recruited adapters and its ability to carry out efficient recruitment at low to medium concentrations of tyrosine phosphorylated sites. This is consistent with earlier observations that the HER2/HER3 heterodimer represents the most potent mitogenic signaling pair [2].

Bottom Line: EGFR-type receptor tyrosine kinases achieve a broad spectrum of cellular responses by utilizing a set of structurally conserved building blocks.Based on available crystal structures and biochemical information, significant new insights have emerged into modes of receptor control, its deregulation in cancer, and the nuances that differentiate the four human receptors.This review gives an overview of current models of the control of receptor activity with a special emphasis on HER2 and HER3.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of California Los Angeles, Department of Medicine, Hematology-Oncology and Biological Chemistry, Molecular Biology Institute, Los Angeles, California 90095-1678, USA. rlandgraf@mednet.ucla.edu

ABSTRACT
EGFR-type receptor tyrosine kinases achieve a broad spectrum of cellular responses by utilizing a set of structurally conserved building blocks. Based on available crystal structures and biochemical information, significant new insights have emerged into modes of receptor control, its deregulation in cancer, and the nuances that differentiate the four human receptors. This review gives an overview of current models of the control of receptor activity with a special emphasis on HER2 and HER3.

Show MeSH
Related in: MedlinePlus