Targeted disruption of PKC from AKAP signaling complexes.
Targeted disruption of PKC from AKAP signaling complexes.
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DOI：
10.1039/d1cb00106j
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发表时间：
2021-08-05
影响因子：
4.1
通讯作者：
Kennedy EJ
中科院分区：
文献类型：
--
作者：
Limaye AJ;Bendzunas GN;Kennedy EJ
蛋白激酶C （PKC）是AGC激酶亚家族的一员，调节多种信号通路和生理过程。涉及PKC及其支架伙伴的蛋白质-蛋白质相互作用决定了PKC活性的时空动态，包括其激活第二信使分子和潜在底物的途径。虽然A激酶锚定蛋白（AKAP）支架蛋白家族普遍结合PKA，但也发现了一些支架PKC，从而调节其催化输出。靶向这些支架相互作用可以进一步阐明亚细胞区隔化对PKC信号传导的影响。在这里，我们报道了两种碳氢化合物钉接肽CSTAD5和CSTAD6的发展，它们具有细胞渗透性并结合PKC以破坏细胞中PKC - gravin复合物的形成。两种抑制肽下调pma诱导的由PKC-gravin复合物介导的细胞骨架重塑。此外，这些肽下调PKC底物磷酸化和细胞运动。据我们所知，之前没有报道过PKC选择性AKAP干扰物，因此CSTAD5和CSTAD6是AKAP构建PKC的新干扰物，可以作为解剖AKAP定位PKC信号的有力工具。我们报道了AKAP衍生的构象约束肽的开发，旨在探测AKAP定位的PKC。前导肽CSTAD5和CSTAD6渗透细胞，结合PKC，通过akap破坏其支架，抑制其支架活性。
Protein Kinase C (PKC) is a member of the AGC subfamily of kinases and regulates a wide array of signaling pathways and physiological processes. Protein–protein interactions involving PKC and its scaffolding partners dictate the spatiotemporal dynamics of PKC activity, including its access to activating second messenger molecules and potential substrates. While the A Kinase Anchoring Protein (AKAP) family of scaffold proteins universally bind PKA, several were also found to scaffold PKC, thereby serving to tune its catalytic output. Targeting these scaffolding interactions can further shed light on the effect of subcellular compartmentalization on PKC signaling. Here we report the development of two hydrocarbon stapled peptides, CSTAD5 and CSTAD6, that are cell permeable and bind PKC to disrupt PKC–gravin complex formation in cells. Both constrained peptides downregulate PMA-induced cytoskeletal remodeling that is mediated by the PKC–gravin complex as measured by cell rounding. Further, these peptides downregulate PKC substrate phosphorylation and cell motility. To the best of our knowledge, no PKC-selective AKAP disruptors have previously been reported and thus CSTAD5 and CSTAD6 are novel disruptors of PKC scaffolding by AKAPs and may serve as powerful tools for dissecting AKAP-localized PKC signaling. We report the development of AKAP derived, conformationally constrained peptides designed to probe AKAP-localized PKC. The lead peptides, CSTAD5 and CSTAD6 permeate cells, bind PKC, disrupt its scaffolding by AKAPs to inhibit its scaffolded activity.
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DOI：
10.1155/2012/529179
发表时间：
2012
期刊：
Journal of signal transduction
影响因子：
--
作者：
Akakura S;Gelman IH
通讯作者：
Gelman IH
影响因子：
4.8
作者：
Carlson, Cathrine Rein;Lygren, Birgitte;Scott, John D.
通讯作者：
Scott, John D.
DOI：
10.1007/978-1-4939-2537-7_11
发表时间：
2015-01-01
期刊：
CAMP SIGNALING: METHODS AND PROTOCOLS
影响因子：
--
作者：
Kennedy, Eileen J.;Scott, John D.
通讯作者：
Scott, John D.
影响因子：
5
作者：
Liron, Tamar;Chen, Leon E.;Mochly-Rosen, Daria
通讯作者：
Mochly-Rosen, Daria
影响因子：
3.2
作者：
Autenrieth, Karolin;Bendzunas, N. George;Kennedy, Eileen J.
通讯作者：
Kennedy, Eileen J.