GPSM1

更新于：2025-05-07

基本信息

别名

Activator of G-protein signaling 3、AGS3、DKFZP727I051

+ [3]

简介

Guanine nucleotide dissociation inhibitor (GDI) which functions as a receptor-independent activator of heterotrimeric G-protein signaling. Keeps G(i/o) alpha subunit in its GDP-bound form thus uncoupling heterotrimeric G-proteins signaling from G protein-coupled receptors. Controls spindle orientation and asymmetric cell fate of cerebral cortical progenitors. May also be involved in macroautophagy in intestinal cells. May play a role in drug addiction.

关联

项与 GPSM1 相关的药物

AN-465 / 42243987

靶点

GPSM1

作用机制

GPSM1 inhibitors

在研机构

上海交通大学医学院

原研机构

上海交通大学医学院

在研适应症

2型糖尿病 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 GPSM1 相关的临床结果

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100 项与 GPSM1 相关的转化医学

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0 项与 GPSM1 相关的专利（医药）

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项与 GPSM1 相关的文献（医药）

2025-03-01·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

GPSM1 interacts and cooperates with MMP19 to promote proliferation and EMT in colorectal cancer cells

Article

作者: Chen, Yang ; Xing, Xiaoming ; Wang, Lu ; Qiao, Yehua ; Zhao, Han ; Song, Yaolin ; Li, Na ; Ran, Wenwen ; Li, Guangqi ; Zhang, Xiangyan

Among patients with colorectal cancer (CRC), metastasis accounts for the majority of deaths, and epithelial-mesenchymal transition (EMT) is important in the metastatic process. However, the mechanism underlying the correlation between the two in CRC is unknown. Here, we verified that a receptor-independent protein, G-protein signaling modulator 1 (GPSM1), was increased in CRC and had a significant positive correlation with matrix metalloproteinase 19 (MMP19). GPSM1 and MMP19 knockdown or overexpression decreased and increased proliferation, migration and invasion of CRC cells, respectively. In addition, overexpression or knockdown of GPSM1 and MMP19 upregulated and inhibited EMT, respectively. Interfering with MMP19 reversed EMT activation via GPSM1 overexpression. Apoptosis was induced by GPSM1 and MMP19 knockdown and activated the caspase3/Bcl-2/Bax signaling pathway. In conclusion, these results support the role of GPSM1 and MMP19 in CRC progression.

2025-02-17·Critical Reviews in Clinical Laboratory Sciences

Genetic variants of accessory proteins and G proteins in human genetic disease

Review

作者: Chidiac, Peter ; Gorvin, Caroline M. ; Jose, Pedro A. ; Thompson, Miles D. ; Hauser, Alexander S.

We present a series of three articles on the genetics and pharmacogenetics of G protein- coupled receptors (GPCR). In the first article, we discuss genetic variants of the G protein subunits and accessory proteins that are associated with human phenotypes; in the second article, we build upon this to discuss "G protein-coupled receptor (GPCR) gene variants and human genetic disease" and in the third article, we survey "G protein-coupled receptor pharmacogenomics". In the present article, we review the processes of ligand binding, GPCR activation, inactivation, and receptor trafficking to the membrane in the context of human genetic disease resulting from pathogenic variants of accessory proteins and G proteins. Pathogenic variants of the genes encoding G protein α and β subunits are examined in diverse phenotypes. Variants in the genes encoding accessory proteins that modify or organize G protein coupling have been associated with disease; these include the contribution of variants of the regulator of G protein signaling (RGS) to hypertension; the role of variants of activator of G protein signaling type III in phenotypes such as hypoxia; the contribution of variation at the RGS10 gene to short stature and immunological compromise; and the involvement of variants of G protein-coupled receptor kinases (GRKs), such as GRK4, in hypertension. Variation in genes that encode proteins involved in GPCR signaling are outlined in the context of the changes in structure and function that may be associated with human phenotypes.

2025-02-01·Journal for ImmunoTherapy of Cancer

Disruption of GPSM1/CSF1 signaling reprograms tumor-associated macrophages to overcome anti-PD-1 resistance in colorectal cancer

Article

作者: Xing, Xiaoming ; Chen, Yang ; Li, Na ; Xiao, Yujing ; Jia, Huiqing ; Zhao, Han ; Yao, Yifan ; Zhang, Xiangyan

BackgroundImmune checkpoint blockade (ICB) therapies, particularly anti-PD-1, benefit only a limited subset of colorectal cancer (CRC) patients. G-protein signaling modulator 1 (GPSM1) is implicated in immunity and oncology, yet its role in regulating the CRC tumor microenvironment (TME) and contributing to anti-PD-1 resistance remains poorly understood.MethodsWe employed single-cell RNA sequencing and multiplex immunofluorescence on tumor samples from anti-PD-1-resistant CRC patients to evaluate GPSM1 expression and its impact on macrophage polarization. An orthotopic CRC xenograft model in C57BL/6 mice was used to assess the role of GPSM1 in vivo. An in vitro co-culture system, alongside mass cytometry and flow cytometry, explored GPSM1’s biological functions within the TME. We further used ChIP-PCR, mass spectrometry, and co-immunoprecipitation to elucidate the mechanisms regulating GPSM1 activity.ResultsGPSM1 expression was significantly elevated in anti-PD-1-resistant CRC tissues. Enhanced GPSM1 levels promoted anti-PD-1 resistance by driving macrophage polarization toward an immunosuppressive M2 phenotype, facilitating their infiltration into the TME. We identified the deubiquitinase USP9X as a key factor preventing GPSM1 degradation through K63-polyubiquitination. This stabilization of GPSM1 led to MEIS3 nuclear translocation, activating macrophage colony-stimulating factor expression. Importantly, ruxolitinib emerged as a promising GPSM1-targeting candidate, demonstrating improved efficacy in combination with anti-PD-1 therapy in both microsatellite instability-high and microsatellite stable CRC models.ConclusionsOur findings highlight the pivotal role of GPSM1-driven M2 macrophage infiltration in mediating anti-PD-1 resistance in CRC. Targeting GPSM1 offers a novel therapeutic strategy to enhance ICB efficacy, potentially broadening the patient population that may benefit from these therapies.