6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases

Wood, Edgar R.; Shewchuk, Lisa M.; Ellis, Byron; Brignola, Perry S.; Brashear, Ronald L.; Caferro, Thomas R.; Dickerson, Scott H.; Dickson, Hamilton D.; Donaldson, Kelly H.; Gaul, Michael D.; Griffin, Robert J.; Hassell, Anne M.; Keith, Barry R.; Mullin, Robert J.; Petrov, Kimberly G.; Reno, Michael J.; Rusnak, David W.; Tadepalli, Sarva M.; Ulrich, John C.; Wagner, Craig D.; Vanderwall, Dana E.; Waterson, Alex G.; Williams, Jon D.; White, Wendy L.; Uehling, David

doi:10.1073/pnas.0708281105

Cited by 95 publications

(98 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3C,D), apparently stabilizing asymmetric interactions between the two TKDs (Red Brewer et al 2009). A similar arrangement was also reported in asymmetric ErbB4 TKD dimers (Wood et al 2008). Based on these structures, residues 664-672 are considered to constitute a "juxtamembrane latch" (Jura et al 2009a), enhancing EGFR activation by promoting formation of the asymmetric dimer.…”

Section: The Intracellular Juxtamembrane (Ijm) Regionmentioning

confidence: 85%

The EGFR Family: Not So Prototypical Receptor Tyrosine Kinases

Lemmon

Schlessinger

Ferguson

2014

Cold Spring Harbor Perspectives in Biology

380

367

View full text Add to dashboard Cite

The epidermal growth factor receptor (EGFR) was among the first receptor tyrosine kinases (RTKs) for which ligand binding was studied and for which the importance of ligand-induced dimerization was established. As a result, EGFR and its relatives have frequently been termed "prototypical" RTKs. Many years of mechanistic studies, however, have revealed that-far from being prototypical-the EGFR family is quite unique. As we discuss in this review, the EGFR family uses a distinctive "receptor-mediated" dimerization mechanism, with ligand binding inducing a dramatic conformational change that exposes a dimerization arm. Intracellular kinase domain regulation in this family is also unique, being driven by allosteric changes induced by asymmetric dimer formation rather than the more typical activationloop phosphorylation. EGFR family members also distinguish themselves from other RTKs in having an intracellular juxtamembrane (JM) domain that activates (rather than autoinhibits) the receptor and a very large carboxy-terminal tail that contains autophosphorylation sites and serves an autoregulatory function. We discuss recent advances in mechanistic aspects of all of these components of EGFR family members, attempting to integrate them into a view of how RTKs in this important class are regulated at the cell surface.

show abstract

Section: The Intracellular Juxtamembrane (Ijm) Regionmentioning

confidence: 85%

The EGFR Family: Not So Prototypical Receptor Tyrosine Kinases

Lemmon

Schlessinger

Ferguson

2014

Cold Spring Harbor Perspectives in Biology

380

367

View full text Add to dashboard Cite

show abstract

“…B, contacts made by residues in mutation A. The Her4 donor monomer is shown in blue, and the PQPP and PQRY sequences in it are highlighted in yellow (structure shown is PDB ID: 2R4B) (17). The Her4 acceptor monomer is shown as a green surface.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple crystal structures of the EGFR tyrosine kinase domain have been solved (reviewed in Ref. 15), and in 2008, two structures of the Her4 tyrosine kinase domain were published (16,17). An important advance in the understanding of how ErbB receptor dimerization activates the tyrosine kinase domain came from the crystal structure of an EGFR kinase domain dimer (18).…”

mentioning

confidence: 99%

Her4 and Her2/neu Tyrosine Kinase Domains Dimerize and Activate in a Reconstituted in Vitro System

Monsey

Shen

Schlesinger

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Her4 (ErbB-4) and Her2/neu (ErbB-2) are receptor-tyrosine kinases belonging to the epidermal growth factor receptor (EGFR) family. Crystal structures of EGFR and Her4 kinase domains demonstrate kinase dimerization and activation through an allosteric mechanism. The kinase domains form an asymmetric dimer, where the C-lobe surface of one monomer contacts the N-lobe of the other monomer. EGFR kinase dimerization and activation in vitro was previously reported using a nickel-chelating lipid-liposome system, and we now apply this system to all other members of the EGFR family. Polyhistidinetagged Her4, Her2/neu, and Her3 kinase domains are bound to these nickel-liposomes and are brought to high local concentration, mimicking what happens to full-length receptors in vivo following ligand binding. Addition of nickel-liposomes to Her4 kinase domain results in 40-fold activation in kinase activity and marked enhancement of C-terminal tail autophosphorylation. Activation of Her4 shows a sigmoidal dependence on kinase concentration, consistent with a cooperative process requiring kinase dimerization. Her2/neu kinase activity is also activated by nickel-liposomes, and is increased further by heterodimerization with Her3 or Her4. The ability of Her3 and Her4 to heterodimerize and activate other family members is studied in vitro. Her3 kinase domain readily activates Her2/neu but is a poor activator of Her4, which differs from the prediction made by the asymmetric dimer model. Mutation of Her3 residues 952 ENI 954 to the corresponding sequence in Her4 enhanced the ability of Her3 to activate Her4, demonstrating that sequence differences on the C-lobe surface influence the heterodimerization and activation of ErbB kinase domains.Her4 (ErbB-4) and Her2/neu (ErbB-2) are members of the ErbB family of receptor-tyrosine kinases, with the founding member of this family being epidermal growth factor receptor (EGFR) 3 (1). The ErbB receptor-tyrosine kinases have an extracellular domain that is involved in ligand binding and receptor homo-or heterodimerization. Their intracellular domain consists of the juxtamembrane region, tyrosine kinase domain, and C-terminal tail. EGFR, Her2/neu, and Her4 contain catalytically active kinase domains, whereas Her3 (ErbB-3) has an inactive kinase domain and must heterodimerize with another ErbB receptor to signal (2). Several studies on ErbB heterodimerization have shown that Her2/neu is the preferred heterodimerization partner for the other three ErbB receptors (3-5). These studies also provide evidence for formation of EGFR-Her3 and EGFR-Her4 heterodimers in response to ligands that bind to Her3 or Her4 (3, 6). Both Her4 and Her2/neu play important roles in the development and the normal physiology of the cardiovascular and nervous systems (7,8). Her4 and Her2/neu knock-out mice both die around embryonic day 10.5 because of malformation of the cardiac trabeculae, and additionally, they are found to have abnormalities in the hindbrain or in sensory ganglia and motor nerves (9, 10). In human breast ...

show abstract

“…Jura et al (15) noted a similar latch between the activator and receiver kinase in a previously reported crystal structure of the related ErbB4 kinase domain (16). By assaying several soluble, truncated forms of the intracellular kinase domain, they verified the importance of the juxtamembrane domain in kinase activation.…”

mentioning

confidence: 65%

Asp-960/Glu-961 Controls the Movement of the C-terminal Tail of the Epidermal Growth Factor Receptor to Regulate Asymmetric Dimer Formation

Yang

Macdonald-Obermann

Piwnica‐Worms

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The epidermal growth factor (EGF) receptor is a tyrosine kinase that dimerizes in response to ligand binding. Ligand-induced dimerization of the extracellular domain of the receptor promotes formation of an asymmetric dimer of the intracellular kinase domains, leading to stimulation of the tyrosine kinase activity of the receptor. We recently monitored ligand-promoted conformational changes within the EGF receptor in real time using luciferase fragment complementation imaging and showed that there was significant movement of the C-terminal tail of the EGF receptor following EGF binding (Yang, K. S., Ilagan, M. X. G., Piwnica-Worms, D., and Pike, L. J. (2009) J. Biol. Chem. 284, 7474 -7482). To investigate the structural basis for this conformational change, we analyzed the effect of several mutations on the kinase activity and luciferase fragment complementation activity of the EGF receptor. Mutation of Asp-960 and Glu-961, two residues at the beginning of the C-terminal tail, to alanine resulted in a marked enhancement of EGFstimulated kinase activity as well as enhanced downstream signaling. The side chain of Asp-960 interacts with that of Ser-787. Mutation of Ser-787 to Phe, which precludes this interaction, also leads to enhanced receptor kinase activity. Our data are consistent with the hypothesis that Asp-960/Glu-961 represents a hinge or fulcrum for the movement of the C-terminal tail of the EGF receptor. Mutation of these residues destabilizes this hinge, facilitating the formation of the activating asymmetric dimer and leading to enhanced receptor signaling. The epidermal growth factor (EGF)2 receptor is a classical receptor-tyrosine kinase composed of an extracellular ligand binding domain and an intracellular tyrosine kinase domain (1). In its inactive state, the EGF receptor is thought to exist in membranes as a monomer (2, 3), although substantial evidence suggests that it also forms inactive "pre-dimers" (4 -8). Binding of EGF induces a major conformational change in the extracellular domain of the receptor allowing the formation of back-toback receptor dimers (9 -11). This leads to the activation of the intracellular tyrosine kinase domain.Recent studies have provided insight into the mechanism through which receptor dimerization leads to activation of the tyrosine kinase. Zhang et al. (12) reported that the EGF receptor kinase domain crystallizes as an asymmetric dimer in which the C-lobe of one kinase (the activator kinase) interacts with the N-lobe of the second kinase (the receiver kinase). Through mutational analysis, they demonstrated that the receiver kinase becomes activated as a result of asymmetric dimer formation. Subsequently, Thiel et al. (13) presented evidence that the intracellular juxtamembrane domain was involved in this allosteric activation of the EGF receptor kinase domain. The role of the juxtamembrane domain in dimer formation was clarified by Brewer et al. (14) who reported the crystal structure of an EGF receptor asymmetric kinase dimer that contained essentially all of...

show abstract

6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases

Cited by 95 publications

References 12 publications

The EGFR Family: Not So Prototypical Receptor Tyrosine Kinases

The EGFR Family: Not So Prototypical Receptor Tyrosine Kinases

Her4 and Her2/neu Tyrosine Kinase Domains Dimerize and Activate in a Reconstituted in Vitro System

Asp-960/Glu-961 Controls the Movement of the C-terminal Tail of the Epidermal Growth Factor Receptor to Regulate Asymmetric Dimer Formation

Contact Info

Product

Resources

About