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

Koga, Fumitaka; Xu, Wanping; Karpova, Tatiana S.; McNally, James G.; Baron, Roland; Neckers, Len

doi:10.1073/pnas.0604705103

Cited by 109 publications

(132 citation statements)

References 38 publications

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“…S1B). The latency of Akt activation compared to activation of Src suggests that the former could be Src-dependent, as we previously reported in bladder and breast cancer cells (8). That the Src inhibitor PP1 fully blocked 17-AAG-induced Akt activation (Fig.…”

Section: -Aag Promotes Osteoclastogenesis Through Src Kinase Activasupporting

confidence: 48%

“…This phenomenon has also been observed for the RNA-dependent serine-threonine kinases PKR and Raf-1 (9,10) and for the tyrosine kinase ErbB2 (11). Such transient activation, although short-lived itself, can in certain cases propagate a downstream signaling cascade of much longer duration (8).…”

mentioning

confidence: 85%

“…Recently, we demonstrated that Hsp90 interaction maintains the client protein c-Src in a metastable state, intermediate between active and inactive conformations (8). Disruption of Hsp90-c-Src association by exposure to 17-AAG results in transient Src kinase activation before Src destabilization and degradation.…”

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confidence: 99%

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Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Yano

Tsutsumi

Soga

et al. 2008

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

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Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells in vitro and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Srcdependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy.cancer ͉ geldanamycin ͉ heat shock protein 90 ͉ osteoclastogenesis

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Section: -Aag Promotes Osteoclastogenesis Through Src Kinase Activasupporting

confidence: 48%

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confidence: 85%

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Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Yano

Tsutsumi

Soga

et al. 2008

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

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“…Hsp90 is thought to direct the folding of Src kinases into the inactive conformation, which prevents their degradation (Xu and Lindquist, 1993;Xu et al, 1999). Interestingly, inhibition of Hsp90 with GA rapidly disrupts Src association with Hsp90, leading to transient activation of c-Src (Koga et al, 2006). We now demonstrated that Hsp90 is also a bona fide Src substrate in response to VEGFR-2 activation, which results in activation of Hsp90, suggesting a reciprocal influence between the two proteins that regulates both their activity in endothelial cells.…”

Section: Discussionmentioning

confidence: 64%

Src-mediated Phosphorylation of Hsp90 in Response to Vascular Endothelial Growth Factor (VEGF) Is Required for VEGF Receptor-2 Signaling to Endothelial NO Synthase

Duval

Bœuf

Huot

et al. 2007

MBoC

132

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Nitric oxide (NO) release from endothelial cells, via endothelial NO synthase (eNOS) activation, is central to the proangiogenic actions of vascular endothelial growth factor (VEGF). VEGF signaling to eNOS is principally mediated byan Akt-dependent phosphorylation of eNOS and by increased association of eNOS to the molecular chaperone, heatshock protein 90 kDa (Hsp90). Herein, we report that VEGFR-2 activation induces tyrosine phosphorylation of VEGF receptor 2 (VEGFR-2)-associated Hsp90␤. Tyrosine phosphorylation of Hsp90␤ in response to VEGF is dependent on internalization of the VEGFR-2 and on Src kinase activation. Furthermore, we demonstrate that c-Src directly phosphorylates Hsp90 on tyrosine 300 residue and that this event is essential for VEGF-stimulated eNOS association to Hsp90 and thus NO release from endothelial cells. Our work identifies Y300 phosphorylation of Hsp90 as a novel regulated posttranslational modification of the chaperone and demonstrates its importance in the proangiogenic actions of VEGF, namely by regulating NO release from endothelial cells. INTRODUCTIONVascular endothelial growth factor (VEGF) is a potent proangiogenic cytokine that activates three specific receptor tyrosine kinases (RTK): VEGF receptor (VEGFR)-1, -2, and -3. Gene knockout studies revealed that VEGF and VEGFRs are essential for the development of the vasculature in mouse embryos (Fong et al., 1995;Shalaby et al., 1995;Carmeliet et al., 1996;Dumont et al., 1998). In addition to its functional roles in vasculogenesis, VEGF plays key roles in adult physiological and pathological angiogenesis such as wound healing and tumor vascularization. VEGFR-2 mediates most of the functional and biochemical effects of VEGF in endothelial cells including proliferation, migration, survival, and nitric oxide (NO) release. These effects are produced through the activation of multiple signaling pathways, such as the phosphoinositide-3 kinase (PI-3 kinase)/ Akt, p38 mitogen-activated protein kinase (MAPK), phospholipase C (PLC)-␥, and Erk/MAPK, after the activation of VEGFR-2 (Rousseau et al., 1997;Takahashi and Shibuya, 1997;Gerber et al., 1998;Takahashi et al., 2001). VEGF-mediated activation of the Ser/Thr kinase Akt leads to phosphorylation of serine 1179 on bovine endothelial NO synthase (eNOS; Ser 1177 in the human form), which increases eNOS catalytic activity and results in release of NO from endothelial cells (Fulton et al., 1999;Dimmeler et al., 1999). In turn, NO released from endothelium contributes to the proangiogenic effects of VEGF. Indeed, VEGF-mediated vascular permeability, angiogenesis, and endothelial cell precursor mobilization are markedly impaired in eNOS-deficient mice (Fukumura et al., 2001;Aicher et al., 2003).Heat-shock protein 90 kDa (Hsp90) is a multifunctional molecular chaperone, and its role in the prevention of protein aggregation and in the refolding of denatured proteins has been studied in much detail (Whitesell and Lindquist, 2005). Hsp90 is also a regulator of the activity of signaling molecules su...

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“…Previous studies have shown that HSP90 inhibition reduces activation of Akt and ERK, which are downstream of multiple clients of HSP90, contributes to induction of apoptosis (24,47,48). In particular, Akt itself is known to be a HSP90 client protein (49).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress

Wang

Guo

Wang

et al. 2016

Molecular Cancer Therapeutics

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Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy.

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

Cited by 109 publications

References 38 publications

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Src-mediated Phosphorylation of Hsp90 in Response to Vascular Endothelial Growth Factor (VEGF) Is Required for VEGF Receptor-2 Signaling to Endothelial NO Synthase

Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress

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