Molecular Mechanism of 17-Allylamino-17-demethoxygeldanamycin (17-AAG)-induced AXL Receptor Tyrosine Kinase Degradation

Krishnamoorthy, Gnana P.; Guida, Teresa; Alfano, Luigi; Avilla, Elvira; Santoro, Massimo; Carlomagno, Francesca; Melillo, Rosa Marina

doi:10.1074/jbc.m112.439422

Cited by 48 publications

(40 citation statements)

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“…These bindings are crucial for cellular fate of NCC [38]. CHIP overexpression controls stability and promotes the degradation of several target proteins as the apoptosis suppressor (DDIAS), the potassium channel Kv1.5, the receptor tyrosine kinase AXL and several others [50-52]. We found here that overexpression of CHIP in MCD4 cells significantly decreased AQP2 abundance within one hour after CHX incubation.…”

Section: Discussionmentioning

confidence: 69%

“…Client proteins of CHIP can be targeted either to lysosomes or to proteasomes for degradation [50, 54]. While short-chain ubiquitylation increases AQP2 endocytosis and lysosomal degradation [22], polyubiquitylation targets AQP2 to proteasomes, in fact MG132 treatment increased the stability of AQP2 by impairing its proteasomal degradation [23].…”

Section: Discussionmentioning

confidence: 99%

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AQP2 Abundance is Regulated by the E3-Ligase CHIP Via HSP70

Centrone

Ranieri

Mise

et al. 2017

Cell Physiol Biochem

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Background/Aims: AQP2 expression is mainly controlled by vasopressin-dependent changes in protein abundance which is in turn regulated by AQP2 ubiquitylation and degradation, however the proteins involved in these processes are largely unknown. Here, we investigated the potential role of the CHIP E3 ligase in AQP2 regulation. Methods: MCD4 cells and kidney slices were used to study the involvement of the E3 ligase CHIP on AQP2 protein abundance by cell homogenization and immunoprecipitation followed by immunoblotting. Results: We found that AQP2 complexes with CHIP in renal tissue. Expression of CHIP increased proteasomal degradation of AQP2 and HSP70 abundance, a molecular signature of HSP90 inhibition. Increased HSP70 level, secondary to CHIP expression, promoted ERK signaling resulting in increased AQP2 phosphorylation at S261. Phosphorylation of AQP2 at S256 and T269 were instead downregulated. Next, we investigated HSP70 interaction with AQP2, which is important for endocytosis. Compared with AQP2-wt, HSP70 binding decreased in AQP2-S256D and AQP2-S256D-S261D, while increased in AQP2-S256D-S261A. Surprisingly, expression of CHIP-delUbox, displaying a loss of E3 ligase activity, still induced AQP2 degradation, indicating that CHIP does not ubiquitylate and degrade AQP2 itself. Conversely, the AQP2 half-life was increased upon the expression of CHIP-delTPR a domain which binds Hsc70/HSP70 and HSP90. HSP70 has been reported to bind other E3 ligases such as MDM2. Notably, we found that co-expression of CHIP and MDM2 increased AQP2 degradation, whereas co-expression of CHIP with MDM2-delRING, an inactive form of MDM2, impaired AQP2 degradation. Conclusion: Our findings indicate CHIP as a master regulator of AQP2 degradation via HSP70 that has dual functions: (1) as chaperone for AQP2 and (2) as an anchoring protein for MDM2 E3 ligase, which is likely to be involved in AQP2 degradation.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

AQP2 Abundance is Regulated by the E3-Ligase CHIP Via HSP70

Centrone

Ranieri

Mise

et al. 2017

Cell Physiol Biochem

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“…Geldanamycin elicits the Ub-dependent degradation of several metastable PM tyrosine receptor kinases (e.g., ErbB2, Ron, EGF, Met, and EphA2) as a consequence of the unfolding of their catalytic domains (72,129,153). Ubiquitination of these kinases is usually facilitated by the recruitment of the COOH terminus of Hsc70 interacting protein (CHIP) via Hsc70/Hsp70, which is upregulated upon Hsp90 inhibition as a consequence of cellular stress response (22).…”

Section: Cytoplasmic Domain Recognitionmentioning

confidence: 99%

Protein Homeostasis at the Plasma Membrane

Apaja

Lukacs

2014

Physiology

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The plasma membrane (PM) and endocytic protein quality control (QC) in conjunction with the endosomal sorting machinery either repairs or targets conformationally damaged membrane proteins for lysosomal/vacuolar degradation. Here, we provide an overview of emerging aspects of the underlying mechanisms of PM QC that fulfill a critical role in preserving cellular protein homeostasis in health and diseases.

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“…Tumor cells are more dependent on Hsp90 than normal counterparts, and its pharmacological manipulation in order to interfere with the folding and conformational stability of client proteins has been shown to elicit their selective proteolytic degradation [21][22][23][24]. Cks proteins exist in twofolded states, a monomer or a domainswapped dimer, and are thought to interchange between these by way of folding intermediates [25].…”

Section: Introductionmentioning

confidence: 99%