Geldanamycin selectively targets the nascent form of ERBB3 for degradation

Gerbin, C. Sachi; Landgraf, Ralf

doi:10.1007/s12192-009-0166-1

Cited by 19 publications

(21 citation statements)

References 52 publications

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“…Based on the crucial roles of ErbB3‐PI3K‐Akt axis in Met‐amplified HCC827GR cells, we sought to determine whether treatment with WK88‐1 could diminish the expression levels of these oncoproteins. Our findings show that treatment with WK88‐1 downregulates the protein levels of ErbB3 together with other well‐known Hsp90 client proteins including EGFR, ErbB2, Met, and Akt, suggesting that ErbB3 is a potential substrate for Hsp90 as reported . Therefore, these findings provide insight as to how the treatment with WK88‐1 may block alternative cell survival pathways in Met‐amplified HCC827GR cell lines (Fig.…”

Section: Discussionsupporting

confidence: 72%

Anti‐tumor activity of WK88‐1, a novel geldanamycin derivative, in gefitinib‐resistant non‐small cell lung cancers with Met amplification

et al. 2014

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Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been introduced for the treatment of non-small cell lung cancer (NSCLC), the emergence of secondary T790M mutation in EGFR or amplification of the Met proto-oncogene restrain the clinical success of EGFR-TKIs. Since heat shock protein-90 (Hsp90) stabilizes various oncoproteins including EGFR and c-Met, the inhibition of Hsp90 activity appears as a rational strategy to develop anticancer drugs. Despite preclinical efficacy of geldanamycin-anasamycin (GA)-derivatives containing benzoquinone moiety as Hsp90 inhibitors, the hepatotoxicity of these GA-derivatives restricts their therapeutic benefit. We have prepared WK-88 series of GA-derivatives, which lack the benzoquinone moiety. In this study, we have examined the anticancer effects of WK88-1 in Met-amplified- and gefitinib-resistant (HCC827GR) NSCLC cells and its parental HCC827 cells. Treatment with WK88-1 reduced the cell viability in both HCC827 and HCC827GR cells, which was associated with marked decrease in the constitutive expression of Hsp90 client proteins, such as EGFR, ErbB2, ErbB3, Met and Akt. Moreover, WK88-1 attenuated phosphorylation of these Hsp90 client proteins and reduced the anchorage-independent growth of HCC827GR cells. Administration of WK88-1 did not cause hepatotoxicity in animals and significantly reduced the growth of HCC827GR cells xenograft tumors in nude mice. Our study provides evidence that ErbB3 might be a client for Hsp90 in Met-amplified NSCLCs. In conclusion, we demonstrate that inhibition of Hsp90 dampens the activation of EGFR- or c-Met-mediated survival of Met-amplified NSCLCs and that WK88-1 as a Hsp90 inhibitor alleviates gefitinib resistance in HCC827GR cells.

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Section: Discussionsupporting

confidence: 72%

Anti‐tumor activity of WK88‐1, a novel geldanamycin derivative, in gefitinib‐resistant non‐small cell lung cancers with Met amplification

et al. 2014

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“…We previously showed that ERBB3 (HER3), a receptor tyrosine kinase of the EGFR family, falls into the first category, with only a very small portion of ERBB3 at any time being transiently associated with HSP90 during maturation. 62 By contrast, the closely related ERBB2 (HER2) receptor is a well-established representative of proteins requiring HSP90 throughout their life cycle. 63 Before we could utilize this knowledge as a functional test for recombinant CDC37, we needed to establish whether this HSP90-derived interaction pattern also extended to CDC37.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylated and Unphosphorylated Serine 13 of CDC37 Stabilize Distinct Interactions between Its Client and HSP90 Binding Domains

Chen

Landgraf

2015

Biochemistry

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Folding and maturation of most protein kinases require chaperone assistance. In higher eukaryotes, CDC37 is the predominant cochaperone that facilitates the transfer of kinase clients to HSP90. Kinase recognition is thought to occur through the N-terminal domain, which has, thus far, eluded structure determination. Client processing also requires the phosphorylation of the N-terminal tail at Ser13 by protein kinase CK2 (casein kinase 2). How phosphorylation alters the molecular properties of CDC37 is not understood. We show that the phosphorylation at Ser13 induces a large shift toward a more compact structure, based on ANS fluorescence, while modestly increasing secondary structure. Moreover, this transition requires interactions of the N-terminal domain and the remainder of CDC37. The stabilizing property of the phosphorylation event can be recreated in trans by a (phospho-Ser13) peptide derived from the N-terminal tail. However, the phosphorylation-induced transition is not dependent on the transferred phosphate group but rather the loss of serine-like properties at position 13. The complete absence of the N-terminal tail results in reduced secondary structure and unresponsiveness to subsequent addition of peptides. The N-terminal tail may therefore serve as an intramolecular chaperone that ensures that CDC37 assumes one of two readily interconvertible states in a manner that impacts the interaction of the client binding N-domain and the MC-domains, involved in dimerization and HSP90 binding.

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“…Hsp90 inhibition specifically induces the degradation of newly synthesized receptors in the endoplasmic reticulum (109), while the stability of both immature and mature ErbB2 forms appear to be dependent on Hsp90 (111). Very recently it was reported that the degradation of nascent ErbB3 is also induced by Hsp90 inhibition (112). In the case of ErbB2, CHIP has been demonstrated to associate with the receptor following Hsp90 inhibition to mediate its ubiquitination and degradation (111,113).…”

Section: Chip-dependent Erbb2 Degradationmentioning

confidence: 99%

E3 ubiquitin ligases in ErbB receptor quantity control

Carraway

2010

Seminars in Cell & Developmental Biology

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Signaling through ErbB family growth factor receptor tyrosine kinases is necessary for the development and homeostasis of a wide variety of tissue types. However, the intensity of receptormediated cellular signaling must fall within a precise range; insufficient signaling can lead to developmental abnormalities or tissue atrophy, while over-signaling can lead to hyperplastic and ultimately neoplastic events. While a plethora of mechanisms have been described that regulate downstream signaling events, it appears that cells also utilize various mechanisms to regulate their ErbB receptor levels. Such mechanisms are collectively termed "ErbB receptor quantity control." Notably, studies over the past few years have highlighted roles for post-transcriptional processes, particularly protein degradation, in ErbB quantity control. Here the involvement of ErbB-directed E3 ubiquitin ligases is discussed, including Nrdp1-mediated ErbB3 degradation, ErbB4 degradation mediated by Nedd4 family E3 ligases, and CHIP-mediated ErbB2 degradation. The hypothesis is forwarded that protein degradation-based ErbB quantity control mechanisms play central roles in suppressing receptor overexpression in normal cells, and that the loss of such mechanisms could facilitate the onset or progression of ErbB-dependent tumors.

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Geldanamycin selectively targets the nascent form of ERBB3 for degradation

Cited by 19 publications

References 52 publications

Anti‐tumor activity of WK88‐1, a novel geldanamycin derivative, in gefitinib‐resistant non‐small cell lung cancers with Met amplification

Anti‐tumor activity of WK88‐1, a novel geldanamycin derivative, in gefitinib‐resistant non‐small cell lung cancers with Met amplification

Phosphorylated and Unphosphorylated Serine 13 of CDC37 Stabilize Distinct Interactions between Its Client and HSP90 Binding Domains

E3 ubiquitin ligases in ErbB receptor quantity control

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