Mechanism of Activation and Inhibition of the HER4/ErbB4 Kinase

Qiu, Chen; Tarrant, Mary Katherine; Choi, Sung Hee; Sathyamurthy, Aruna; Bose, Ron; Banjade, Sudeep; Pal, Ashutosh; Bornmann, William G.; Lemmon, Mark A.; Cole, Philip A.; Leahy, Daniel J.

doi:10.1016/j.str.2007.12.016

Cited by 164 publications

(172 citation statements)

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“…2A, a solution of 1 μM mant-ATP (plus 5 mM MgCl 2 ) shows little fluorescence when excited at 280 nm, but a significant peak centered at 448 nm appears when 3 μM ErbB-TKD is added. This peak reflects FRET from tryptophans and/or tyrosines in the protein to the bound mant-ATP and is seen only when ErbB3-TKD, MgCl 2 , and mant-ATP are all present in the sample ( (27). Consistent with its reduced autophosphorylation activity (Fig.…”

Section: Resultsmentioning

confidence: 73%

“…3A, the overall structure of ErbB3-TKD 665-1001 closely resembles inactive conformations of the EGFR, ErbB4, and Src kinases (5,27). Helix αC of ErbB3-TKD 665-1001 is displaced from the active site, in the "out" position typically seen in structures of inactive kinases (28).…”

Section: Resultsmentioning

confidence: 88%

“…Jura et al (30) very recently reported an ErbB3-TKD 674-1001 structure [Protein Data Bank (PDB) ID 3KEX] that is essentially identical to that reported here and have confirmed the ability of ErbB3-TKD 674-1001 to function as an allosteric activator of EGFR-TKD in vitro. If the ErbB3-TKD does function as a receiver kinase in ErbB receptor dimers, it must do so through N-lobe interactions distinct from those described for EGFR (5) and ErbB4 (27).…”

Section: Resultsmentioning

confidence: 99%

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ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation

Shi

Telesco

Liu

et al. 2010

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

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412

421

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ErbB3/HER3 is one of four members of the human epidermal growth factor receptor (EGFR/HER) or ErbB receptor tyrosine kinase family. ErbB3 binds neuregulins via its extracellular region and signals primarily by heterodimerizing with ErbB2/HER2/Neu. A recently appreciated role for ErbB3 in resistance of tumor cells to EGFR/ErbB2-targeted therapeutics has made it a focus of attention. However, efforts to inactivate ErbB3 therapeutically in parallel with other ErbB receptors are challenging because its intracellular kinase domain is thought to be an inactive pseudokinase that lacks several key conserved (and catalytically important) residuesincluding the catalytic base aspartate. We report here that, despite these sequence alterations, ErbB3 retains sufficient kinase activity to robustly trans-autophosphorylate its intracellular regionalthough it is substantially less active than EGFR and does not phosphorylate exogenous peptides. The ErbB3 kinase domain binds ATP with a K d of approximately 1.1 μM. We describe a crystal structure of ErbB3 kinase bound to an ATP analogue, which resembles the inactive EGFR and ErbB4 kinase domains (but with a shortened αC-helix). Whereas mutations that destabilize this configuration activate EGFR and ErbB4 (and promote EGFR-dependent lung cancers), a similar mutation conversely inactivates ErbB3. Using quantum mechanics/molecular mechanics simulations, we delineate a reaction pathway for ErbB3-catalyzed phosphoryl transfer that does not require the conserved catalytic base and can be catalyzed by the "inactive-like" configuration observed crystallographically. These findings suggest that ErbB3 kinase activity within receptor dimers may be crucial for signaling and could represent an important therapeutic target.dimerization | kinase inhibitor | catalytic mechanism | activation loop R eceptor tyrosine kinases (RTKs) from the EGF receptor (EGFR) or ErbB/HER family play important roles in animal development and disease (1) and are the targets of several important therapeutic agents used clinically to treat cancer. Each receptor contains a large extracellular ligand-binding region (targeted by therapeutic antibodies), a single transmembrane helix, and an intracellular tyrosine kinase domain (TKD) that is flanked by juxtamembrane and C-terminal regulatory regions and is targeted by specific small-molecule kinase inhibitors (1, 2). Ligand binding to the extracellular region promotes homo-or heterodimerization of ErbB receptors, leading to allosteric activation of their intracellular kinase domains through the formation of asymmetric dimers (3-5). Within an activated dimer, the C-terminal regulatory tail is trans-autophosphorylated on tyrosines and recruits downstream signaling molecules that contain phosphotyrosine-binding Src homology-2 (SH2) domains.ErbB3/HER3 is unique among the mammalian ErbB receptors in being generally considered as kinase-inactive (6). When first cloned (7,8), amino acid substitutions were noted at two particular sites that are conserved in other known kinases (9). ...

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Section: Resultsmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

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ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation

Shi

Telesco

Liu

et al. 2010

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

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412

421

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“…Remarkably, we found that the inactive HER4 kinase domain also forms a very similar N-lobe dimer [Protein Data Bank (PDB) ID codes 3BBT and 3BBW], although it crystallizes with different lattice symmetry (space group P6 1 for HER4 compared with C2 for the HER3 crystals) (Fig. 4 A and B) (27).…”

Section: Resultsmentioning

confidence: 99%

Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3

Jura¹,

Shan

Cao³

et al. 2009

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

289

312

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The kinase domain of human epidermal growth factor receptor (HER) 3/ErbB3, a member of the EGF receptor (EGFR) family, lacks several residues that are critical for catalysis. Because catalytic activity in EGFR family members is switched on by an allosteric interaction between kinase domains in an asymmetric kinase domain dimer, HER3 might be specialized to serve as an activator of other EGFR family members. We have determined the crystal structure of the HER3 kinase domain and show that it appears to be locked into an inactive conformation that resembles that of EGFR and HER4. Although the crystal structure shows that the HER3 kinase domain binds ATP, we confirm that it is catalytically inactive but can serve as an activator of the EGFR kinase domain. The HER3 kinase domain forms a dimer in the crystal, mediated by hydrophobic contacts between the N-terminal lobes of the kinase domains. This N-lobe dimer closely resembles a dimer formed by inactive HER4 kinase domains in crystal structures determined previously, and molecular dynamics simulations suggest that the HER3 and HER4 N-lobe dimers are stable. The kinase domains of HER3 and HER4 form similar chains in their respective crystal lattices, in which N-lobe dimers are linked together by reciprocal exchange of C-terminal tails. The conservation of this tiling pattern in HER3 and HER4, which is the closest evolutionary homolog of HER3, might represent a general mechanism by which this branch of the HER receptors restricts ligand-independent formation of active heterodimers with other members of the EGFR family.EGFR ͉ human epidermal growth factor receptor 3 ͉ human epidermal growth factor receptor4 ͉ receptor oligomerization

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“…Compelling evidence has revealed that, in contrast with most receptor-tyrosine kinases, phosphorylation of the activation loop is not required for activation of ERBB kinases (9,38). Structural studies have provided evidence that EGFR (39) and ERBB4 (40) kinases are activated through an allosteric mechanism via formation of an asymmetric dimer. Upon dimer formation, the helix ␣C of one kinase domain is restrained to the catalytically competent conformation by the C-lobe of the other.…”

Section: Discussionmentioning

confidence: 99%

Acquired Substrate Preference for GAB1 Protein Bestows Transforming Activity to ERBB2 Kinase Lung Cancer Mutants

Fan

Wong

Marino

et al. 2013

Journal of Biological Chemistry

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Background: Activating ERBB2 mutants drive tumor formation. Results: Oncogenic ERBB2 has a striking substrate preference for GAB1 in vitro, and GAB1 hyper-phosphorylation is required for mutant ERBB2-induced cell signaling and transformation. Conclusion: Acquired substrate preference for GAB1 is critical to the ERBB2 mutant-mediated oncogenesis. Significance: Understanding the activation mechanism of mutant ERBB2s may lead to the development of therapies targeted against these oncogenic kinases.

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Mechanism of Activation and Inhibition of the HER4/ErbB4 Kinase

Cited by 164 publications

References 44 publications

ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation

ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation

Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3

Acquired Substrate Preference for GAB1 Protein Bestows Transforming Activity to ERBB2 Kinase Lung Cancer Mutants

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