Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.
Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.
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DOI：
10.1073/pnas.2213140120
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发表时间：
2023-05-02
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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人类疾病常常源于对外界信号进行感知并传递到细胞内部的机制出现缺陷。现有治疗药物最广泛针对的蛋白质属于一个名为G蛋白偶联受体（GPCRs）的大型细胞表面受体家族，它们通过激活细胞内部的G蛋白来传递外界信号。在此，我们报道了一项令人惊讶的发现：一种合成小分子能够选择性地靶向G蛋白，且不影响其传递来自GPCRs信号的能力。相反，这种小分子破坏了一种与癌症有关的不依赖GPCR的非典型G蛋白信号传导机制。这项工作揭示了一种针对信号传导机制组成部分的替代范例，该范例在健康和疾病状态下的细胞通讯中具有广泛的相关性。
G蛋白偶联受体（GPCRs）对异源三聚体G蛋白（Gαβγ）的激活是一种细胞信号传导的典型机制，是临床批准药物广泛针对的靶点。然而，很明显异源三聚体G蛋白也可通过不依赖GPCR的机制被激活，这些机制作为药物靶点尚未被开发。GIV/Girdin已成为一种典型的G蛋白非GPCR激活因子，可促进癌症转移。在此，我们介绍IGGi - 11，它是一种首创的小分子抑制剂，可抑制异源三聚体G蛋白信号传导的非经典激活。IGGi - 11与G蛋白α亚基（Gαi）结合，特异性地破坏了它们与GIV/Girdin的相互作用，从而阻断了肿瘤细胞中的非经典G蛋白信号传导，并抑制了转移性癌细胞的促侵袭特性。相比之下，IGGi - 11不干扰由GPCRs触发的经典G蛋白信号传导机制。通过揭示小分子能够选择性地使疾病中失调的G蛋白激活的非经典机制失活，这些发现为探索超越靶向GPCRs的G蛋白信号传导治疗方式提供了依据。
Human diseases frequently arise from defects in the mechanisms by which external cues are sensed and relayed to the interior of the cell. The proteins most widely targeted by existing therapeutic agents belong to a large family of cell surface receptors named G-protein-coupled receptors (GPCRs), which relay external cues by activating G-proteins in the interior of cells. Here, we report the surprising discovery of a synthetic small molecule that selectively targets G-proteins without compromising their ability to relay signals from GPCRs. Instead, this small molecule disrupts an atypical, GPCR-independent mechanism of G-protein signaling involved in cancer. This work reveals an alternative paradigm in targeting components of a signaling machinery with broad relevance in cellular communication in health and disease. Activation of heterotrimeric G-proteins (Gαβγ) by G-protein-coupled receptors (GPCRs) is a quintessential mechanism of cell signaling widely targeted by clinically approved drugs. However, it has become evident that heterotrimeric G-proteins can also be activated via GPCR-independent mechanisms that remain untapped as pharmacological targets. GIV/Girdin has emerged as a prototypical non-GPCR activator of G proteins that promotes cancer metastasis. Here, we introduce IGGi-11, a first-in-class small-molecule inhibitor of noncanonical activation of heterotrimeric G-protein signaling. IGGi-11 binding to G-protein α-subunits (Gαi) specifically disrupted their engagement with GIV/Girdin, thereby blocking noncanonical G-protein signaling in tumor cells and inhibiting proinvasive traits of metastatic cancer cells. In contrast, IGGi-11 did not interfere with canonical G-protein signaling mechanisms triggered by GPCRs. By revealing that small molecules can selectively disable noncanonical mechanisms of G-protein activation dysregulated in disease, these findings warrant the exploration of therapeutic modalities in G-protein signaling that go beyond targeting GPCRs.
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DOI：
10.1083/jcb.201506041
发表时间：
2015-09-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Leyme A;Marivin A;Perez-Gutierrez L;Nguyen LT;Garcia-Marcos M
通讯作者：
Garcia-Marcos M
影响因子：
4.6
作者：
DiGiacomo V;de Opakua AI;Papakonstantinou MP;Nguyen LT;Merino N;Blanco-Canosa JB;Blanco FJ;Garcia-Marcos M
通讯作者：
Garcia-Marcos M
影响因子：
4.8
作者：
Garcia-Marcos, Mikel;Jung, Barbara H.;Ghosh, Pradipta
通讯作者：
Ghosh, Pradipta
影响因子：
4.8
作者：
Garcia-Marcos, Mikel;Ghosh, Pradipta;Farquhar, Marilyn G.
通讯作者：
Farquhar, Marilyn G.
影响因子：
4.8
作者：
Leyme, Anthony;Marivin, Arthur;Garcia-Marcos, Mikel
通讯作者：
Garcia-Marcos, Mikel