Novel Interaction between the Co-chaperone Cdc37 and Rho GTPase Exchange Factor Vav3 Promotes Androgen Receptor Activity and Prostate Cancer Growth*

Wu, Fayi; Peacock, Stephanie; Rao, Shuyun; Lemmon, Sandra K.; Burnstein, Kerry L.

doi:10.1074/jbc.m112.390963

Cited by 20 publications

(15 citation statements)

References 59 publications

(76 reference statements)

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“…1B). As expected based on our previous work, these three Vav3 mutants all retained the capacity for androgen-inducible co-activation of FL-AR (35, 37, 41, 46), but additionally, we found that these three Vav3 truncation mutants enhanced the ligand-independent activity of AR-V7 (Fig. 1C-E).…”

Section: Resultssupporting

confidence: 90%

“…This intramolecular interaction is influenced by co-regulators. For example, our lab showed that Vav3 potently increases FL-AR N/C interaction (37,46). We performed mammalian two-hybrid assays with two AR fusion proteins: the AR LBD linked to the Gal4 DNA-binding domain (Gal4DBD-ARLBD) and the AR N-terminus fused to the transcriptional activation domain of VP16 (VP16AD-ARTAD).…”

Section: Resultsmentioning

confidence: 99%

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Targeting AR Variant–Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities

Magani

Peacock

Rice

et al. 2017

Molecular Cancer Research

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Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced PC. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels. Implications This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Targeting AR Variant–Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities

Magani

Peacock

Rice

et al. 2017

Molecular Cancer Research

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“…AR antagonists such as bicalutamide and nilutamide have been used in CRPC for 3 decades. Unfortunately, the duration of response to these anti-androgens is often less than 4 months; their AR binding is reversible, and paradoxical agonism of the AR occurs in 10 to 15% of patients (32). Two most recently FDA-approved drugs to treat CRPC are abiraterone and enzalutamide, which improve overall survival for 5 months and 2 months, respectively (4, 5).…”

Section: Discussionmentioning

confidence: 99%

Plk1 Inhibition Enhances the Efficacy of Androgen Signaling Blockade in Castration-Resistant Prostate Cancer

et al. 2014

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Prostate cancer (PCa) is thought to be driven by oxidative stress, lipid metabolism, androgen receptor (AR) signaling and activation of the PI3K/AKT/mTOR pathway, but it is uncertain how they may become coordinated during progression to castration-resistant disease which remains incurable. The mitotic kinase polo-like kinase 1 (Plk1) is elevated in PCa where its expression is linked to tumor grade. Notably, Plk1 signaling and lipid metabolism were identified recently as two of the top five most upregulated pathways in a mouse xenograft model of human PCa. Herein, we show that oxidative stress activates both the PI3K/AKT/mTOR pathway and AR signaling in a Plk1-dependent manner in prostate cells. Inhibition of the PI3K/AKT/mTOR pathway prevented oxidative stress-induced activation of AR signaling. Plk1 modulation also affected cholesterol ester accumulation in PCa via the SREBP pathway. Lastly, Plk1 inhibition enhanced cellular responses to androgen signaling inhibitors (ASI) and overcame ASI resistance in both cultured PCa cells and patient-derived tumor xenografts. Given that activation of AR signaling and the PI3K/AKT/mTOR pathway is sufficient to elevate SREBP-dependent expression of key lipid biosynthesis enzymes in castration-resistant PCa, our findings argued that Plk1 activation was responsible for coordinating and driving these processes to promote and sustain the development of this advanced stage of disease. Overall, our results offer a strong mechanistic rationale to evaluate Plk1 inhibitors in combination drug trials to enhance the efficacy of androgen signaling inhibitors in castration-resistant prostate cancer.

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“…However, at least for the latter, the functional region of CDC37 is distinct from its kinase binding domain. 10 Many oncogenic kinases heavily rely on CDC37 activity. Silencing of CDC37 expression by siRNA or shRNA depletes clients such as ERBB2, cRAF, CDK4, CDK6, and AKT in human colon, breast, and prostate cancer lines.…”

mentioning

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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Novel Interaction between the Co-chaperone Cdc37 and Rho GTPase Exchange Factor Vav3 Promotes Androgen Receptor Activity and Prostate Cancer Growth*

Cited by 20 publications

References 59 publications

Targeting AR Variant–Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities

Targeting AR Variant–Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities

Plk1 Inhibition Enhances the Efficacy of Androgen Signaling Blockade in Castration-Resistant Prostate Cancer

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

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