Phase Separation of a PKA Regulatory Subunit Controls cAMP Compartmentation and Oncogenic Signaling.,Cell

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Phase Separation of a PKA Regulatory Subunit Controls cAMP Compartmentation and Oncogenic Signaling.
Cell ( IF 64.5 ) Pub Date : 2020-08-25 , DOI: 10.1016/j.cell.2020.07.043
Jason Z Zhang ₁ , Tsan-Wen Lu ₂ , Lucas M Stolerman ₃ , Brian Tenner ₄ , Jessica R Yang ₅ , Jin-Fan Zhang ₁ , Martin Falcke ₆ , Padmini Rangamani ₃ , Susan S Taylor ₇ , Sohum Mehta ₄ , Jin Zhang ₈

Affiliation

Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mathematical Cell Physiology, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Department of Physics, Humboldt University, 12489 Berlin, Germany.
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

The fidelity of intracellular signaling hinges on the organization of dynamic activity architectures. Spatial compartmentation was first proposed over 30 years ago to explain how diverse G protein-coupled receptors achieve specificity despite converging on a ubiquitous messenger, cyclic adenosine monophosphate (cAMP). However, the mechanisms responsible for spatially constraining this diffusible messenger remain elusive. Here, we reveal that the type I regulatory subunit of cAMP-dependent protein kinase (PKA), RIα, undergoes liquid-liquid phase separation (LLPS) as a function of cAMP signaling to form biomolecular condensates enriched in cAMP and PKA activity, critical for effective cAMP compartmentation. We further show that a PKA fusion oncoprotein associated with an atypical liver cancer potently blocks RIα LLPS and induces aberrant cAMP signaling. Loss of RIα LLPS in normal cells increases cell proliferation and induces cell transformation. Our work reveals LLPS as a principal organizer of signaling compartments and highlights the pathological consequences of dysregulating this activity architecture.

中文翻译：

PKA 调节亚基的相分离控制 cAMP 区室和致癌信号。

细胞内信号的保真度取决于动态活动结构的组织。空间区隔是 30 多年前首次提出的，以解释尽管汇聚在无处不在的信使环磷酸腺苷 (cAMP) 上，但不同的 G 蛋白偶联受体如何实现特异性。然而，负责空间限制这种可扩散信使的机制仍然难以捉摸。在这里，我们揭示了 cAMP 依赖性蛋白激酶 (PKA) 的 I 型调节亚基 RIα 作为 cAMP 信号传导的函数进行液-液相分离 (LLPS)，形成富含 cAMP 和 PKA 活性的生物分子缩合物，这对于有效的 cAMP 分隔。我们进一步表明，与非典型肝癌相关的 PKA 融合癌蛋白可有效阻断 RIα LLPS 并诱导异常的 cAMP 信号传导。正常细胞中 RIα LLPS 的缺失会增加细胞增殖并诱导细胞转化。我们的工作揭示了 LLPS 作为信号室的主要组织者，并突出了这种活动结构失调的病理后果。

更新日期：2020-09-18

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