Surface charge and hydrophobicity determine ErbB2 binding to the Hsp90 chaperone complex

Xu, Wanping; Yuan, Xitong; Xiang, Zhaoyin; Mimnaugh, Edward G.; Marcu, Monica G.; Neckers, Len

doi:10.1038/nsmb885

Cited by 144 publications

(153 citation statements)

References 38 publications

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“…For the ErbB2 kinase domain, it was found that introducing a negative charge in the αC-β4-loop strongly decreased its Hsp90 dependence (60). Interestingly, in the case of v-Src, the increased Hsp90 dependence cannot be explained by increased hydrophobicity of this region as the R318Q mutation and the presence of other hydrophilic residues in v-Src leaves the αC-β4-loop polar.…”

Section: Discussionmentioning

confidence: 99%

Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90

Boczek

Reefschläger

Dehling

et al. 2015

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

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Hsp90 is a molecular chaperone involved in the activation of numerous client proteins, including many kinases. The most stringent kinase client is the oncogenic kinase v-Src. To elucidate how Hsp90 chaperones kinases, we reconstituted v-Src kinase chaperoning in vitro and show that its activation is ATP-dependent, with the cochaperone Cdc37 increasing the efficiency. Consistent with in vivo results, we find that Hsp90 does not influence the almost identical c-Src kinase. To explain these findings, we designed Src kinase chimeras that gradually transform c-Src into v-Src and show that their Hsp90 dependence correlates with compactness and folding cooperativity. Molecular dynamics simulations and hydrogen/deuterium exchange of Hsp90-dependent Src kinase variants further reveal increased transitions between inactive and active states and exposure of specific kinase regions. Thus, Hsp90 shifts an ensemble of conformations of v-Src toward high activity states that would otherwise be metastable and poorly populated.Cdc37 | kinase activation | metastable states | conformational ensembles | chaperone mechanism

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Section: Discussionmentioning

confidence: 99%

Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90

Boczek

Reefschläger

Dehling

et al. 2015

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

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“…An explanation of this apparent paradox may be found in recent studies detailing the complex structural alterations involved in the process of Src activation. Inactive Src exists in a clamped configuration in which the SH2 domain interacts with the C-terminal phospho-Tyr-529 residue, whereas the SH3 domain covers the kinase domain, sterically obstructing access to the recently identified Hsp90 binding loop (29,30). In addition to dephosphorylation of Tyr-529, interaction with SH2 and͞or SH3 ligands primes Src for activation by relaxing this inhibitory conformation and allowing the kinase to be fully activated by phosphorylation of Tyr-418 in the activation loop (31).…”

Section: Discussionmentioning

confidence: 99%

Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation

Koga

Karpova

et al. 2006

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

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109

112

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Hsp90 plays an essential role in maintaining stability and activity of its clients, including oncogenic signaling proteins that regulate key signal transduction nodes. Hsp90 inhibitors interfere with diverse signaling pathways by destabilizing and attenuating activity of such proteins, and thus they exhibit antitumor activity. However, Hsp90 inhibition has recently been reported to activate Akt and Erk and potentiate Akt activation induced by insulin-like growth factor 1 and insulin, raising the concern that clinical use of Hsp90 inhibitors might promote tumor progression under certain circumstances. Here, we show that the prototypical Hsp90 inhibitor geldanamycin induces Akt and Erk activation that is independent of PTEN status and is mediated by transient activation of Src kinase. Activated Src phosphorylates Cbl, which recruits the p85 subunit of phosphatidylinositol 3-kinase, resulting in phosphatidylinositol 3-kinase activation and eventually the activation of Akt and Erk. We show that geldanamycin rapidly disrupts Src association with Hsp90, suggesting that Src activation results directly from dissociation of the chaperone. These data suggest that, under certain circumstances, dual inhibition of Hsp90 and Src may be warranted.cancer ͉ chaperone ͉ geldanamycin

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“…For example, both ErbB2 and EGFR receptor (ErbB1) are susceptible to degradation in the presence of GA in their nascent chain forms. However, once folded, only ErbB2 remains susceptible while mature EGFR receptor is relatively insensitive to drug treatment [10]. The sequence motifs that mediate this differential sensitivity reside on a loop in the N-lobe of the kinase catalytic domain [11].…”

Section: Introductionmentioning

confidence: 99%

Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context

Theodoraki

Kunjappu

Sternberg

et al. 2007

Experimental Cell Research

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Hsp90 inhibitors are currently in clinical trials for cancer therapy based on their ability to promote proteasomal degradation of oncogenic protein kinases and nuclear receptors. Results from recent studies suggest that cancer cells are more sensitive to these inhibitors than cells from healthy tissues. We analyzed an immortalized cell line Ba/F3, for sensitivity to the Hsp90 inhibitor geldanamycin in the absence and presence of the oncogenic tyrosine fusion kinase NPM-ALK expressed from a retroviral vector. Our results showed that NPM-ALK expression makes Akt and Cdk4 more resistant to degradation in the presence of geldanamycin, and there was a slightly reduced amount of apoptosis. The mechanism underlying the effect of NPM-ALK on Akt stability was probed by comparison of the turnover of the kinase after translation inhibition and geldanamycin treatment. We observed that Akt was degraded more rapidly in the presence of GA than upon translation inhibition without NPM-ALK expression. This suggests that NPM-ALK protects the mature kinase. Furthermore, Akt failed to bind to the Cdc37 chaperone in cells expressing NPMALK, which also correlates with increased Akt stability.

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Surface charge and hydrophobicity determine ErbB2 binding to the Hsp90 chaperone complex

Cited by 144 publications

References 38 publications

Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90

Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90

Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation

Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context

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