Dunn Diana M, Woodford Mark R, Truman Andrew W, Jensen Sandra M, Schulman Jacqualyn, Caza Tiffany, Remillard Taylor C, Loiselle David, Wolfgeher Donald, Blagg Brian S J, Franco Lucas, Haystead Timothy A, Daturpalli Soumya, Mayer Matthias P, Trepel Jane B, Morgan Rhodri M L, Prodromou Chrisostomos, Kron Stephen J, Panaretou Barry, Stetler-Stevenson William G, Landas Steve K, Neckers Len, Bratslavsky Gennady, Bourboulia Dimitra, Mollapour Mehdi
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
Cell Rep. 2015 Aug 11;12(6):1006-18. doi: 10.1016/j.celrep.2015.07.004. Epub 2015 Jul 30.
The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific "client" proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Hsp90 remain unknown. Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity, enhances Hsp90 interaction with kinase clients, and compromises the chaperoning of non-kinase clients such as glucocorticoid receptor and CFTR. Suggesting a regulatory paradigm, we also find that Y223 phosphorylation leads to ubiquitination and degradation of hAha1 in the proteasome. Finally, pharmacologic inhibition of c-Abl prevents hAha1 interaction with Hsp90, thereby hypersensitizing cancer cells to Hsp90 inhibitors both in vitro and ex vivo.
热休克蛋白90（Hsp90）水解ATP的能力对其伴侣功能至关重要。共伴侣蛋白Aha1刺激Hsp90的ATP酶活性，使伴侣功能适应特定的“客户”蛋白。直接调节Aha1与Hsp90结合的细胞内信号传导机制尚不清楚。在此，我们表明c-Abl激酶使人类Aha1（hAha1）中的Y223磷酸化，促进其与Hsp90的相互作用。因此，这导致Hsp90的ATP酶活性增加，增强Hsp90与激酶客户蛋白的相互作用，并损害诸如糖皮质激素受体和囊性纤维化跨膜传导调节因子等非激酶客户蛋白的伴侣作用。我们还发现Y223磷酸化导致hAha1在蛋白酶体中泛素化和降解，这提示了一种调节模式。最后，c-Abl的药理学抑制可阻止hAha1与Hsp90相互作用，从而在体外和体内均使癌细胞对Hsp90抑制剂高度敏感。
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