A single amino acid substitution makes ERK2 susceptible to pyridinyl imidazole inhibitors of p38 MAP kinase

Fox, Ted; Coll, Joyce T.; Xie, Xin; Ford, Pamella J.; Germann, Ursula A.; Porter, Margaret; Pazhanisamy, S.; Fleming, Mark; Galullo, Vincent; Su, Michael; Wilson, Keith

doi:10.1002/pro.5560071102

Cited by 129 publications

(108 citation statements)

References 34 publications

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“…To rule out any nonspecific effects, titration of the ERK2 kinase inhibitors was performed (Figures 2e and f). Dosedependent effects were seen with IC 50 values of 400-600 nM for 5-iodotubercidin and 30-50 nM for U0126, respectively (Fox et al, 1998). Thus, RAR b2 activity is increased by b-arrestin 2 through activation of an ERK2-dependent pathway.…”

Section: Resultsmentioning

confidence: 92%

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β-arrestin 2 modulates the activity of nuclear receptor RAR β2 through activation of ERK2 kinase

2005

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The activity of retinoid receptors activity can be regulated by various extracellular stimuli. In an effort to understand the molecular basis for this phenomenon, the role of b-arrestins was investigated. b-Arrestins constitute a class of proteins involved in the internalization of agonistactivated receptors. They have also been linked to MAPK activation suggesting a direct involvement in signaling cascades. Here, we report that b-arrestin 2 stimulates the transcriptional activation of the retinoid RAR and RXR receptors. Of all the retinoid receptors, the RAR b2 subtype showed the strongest sensitivity to b-arrestin 2 action. Interestingly, this event requires the presence of the MAP kinase ERK2, but not that of JNK or P38. Sitedirected mutagenesis showed that Ser 22 and Leu 217 are critical residues of the RAR b2 receptor through which b-arrestin 2 effects are mediated. More importantly, we demonstrate that the induction of PC12 growth inhibition by Nerve Growth Factor is indeed dependent upon RAR b2 transcriptional activation in a b-arrestin 2-and ERK2-dependent manner.

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Section: Resultsmentioning

confidence: 92%

“…5-Iodotubercidin and U0126 are standard potent competitive inhibitors of ERK2 (Favata et al, 1998;Fox et al, 1998). SB-203580 and JNK inhibitor II are potent inhibitors of p38 (Cuenda et al, 1995) and JNKs (Bennett et al, 2001), respectively.…”

Section: Resultsmentioning

confidence: 99%

β-arrestin 2 modulates the activity of nuclear receptor RAR β2 through activation of ERK2 kinase

2005

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“…Previous studies showed that ppERK2-Q103A was susceptible to inhibitors SB203580 and PP1 analogues (21,26). We therefore asked whether the enhanced basal specific activity of ERK2-Q103A was also sensitive to these inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…Structure-function studies of protein kinases have identified a ''gatekeeper'' residue, which regulates binding of nucleotide and small-molecule inhibitors (17)(18)(19)(20)(21)(22). This residue is located on a conserved ␤5 strand, distal to the active site and adjacent to a hinge region that connects the N-and C-terminal domains of the enzyme.…”

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confidence: 99%

The gatekeeper residue controls autoactivation of ERK2 via a pathway of intramolecular connectivity

Emrick¹,

Lee²,

Starkey

et al. 2006

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

124

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Studies of protein kinases have identified a ''gatekeeper'' residue, which confers selectivity for binding nucleotides and small-molecule inhibitors. We report that, in the MAP kinase ERK2, mutations at the gatekeeper residue unexpectedly lead to autoactivation due to enhanced autophosphorylation of regulatory Tyr and Thr sites within the activation lip that control kinase activity. This occurs through an intramolecular mechanism, indicating that the gatekeeper residue indirectly constrains flexibility at the activation lip, precluding access of the phosphoacceptor residues to the catalytic base. Other residues that interact with the gatekeeper site to form a hydrophobic cluster in the N-terminal domain also cause autoactivation when mutated. Hydrogen-exchange studies of a mutant within this cluster reveal perturbations in the conserved DFG motif, predicting a route for side chain connectivity from the hydrophobic cluster to the activation lip. Mutations of residues along this route support this model, explaining how information about the gatekeeper residue identity can be transmitted to the activation lip. Thus, an N-terminal hydrophobic cluster that includes the gatekeeper forms a novel structural unit, which functions to maintain the ''off'' state of ERK2 before cell signal activation.allostery ͉ autoinhibition ͉ autophosphorylation ͉ hydrogen exchange ͉ MAP kinase

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“…This threonine residue, also called the gatekeeper, is known to be an important determinant of inhibitor binding in the context of multiple kinases (13,18,42,43). Imatinib-resistant mutations at other positions in the ABL kinase tend to weaken binding only moderately, albeit enough to confer clinical resistance.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

Carter

Wodicka

Shah

et al. 2005

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

517

390

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To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved ''gatekeeper'' threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib-and BMS-354825-resistant ABL(T315I) kinase. The KIT͞FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D͞T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitiniband erlotinib-resistant EGFR(L858R͞T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib͞ erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of nextgeneration drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy. drug resistance ͉ gatekeeper mutation ͉ kinase inhibitor

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A single amino acid substitution makes ERK2 susceptible to pyridinyl imidazole inhibitors of p38 MAP kinase

Cited by 129 publications

References 34 publications

β-arrestin 2 modulates the activity of nuclear receptor RAR β2 through activation of ERK2 kinase

β-arrestin 2 modulates the activity of nuclear receptor RAR β2 through activation of ERK2 kinase

The gatekeeper residue controls autoactivation of ERK2 via a pathway of intramolecular connectivity

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

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