Adaptor SH3BGRL promotes breast cancer metastasis through PFN1 degradation by translational STUB1 upregulation

Zhang, Shaoyang; Guo, Xuemin; Liu, Xiufeng; Zhong, Zhixiong; Yang, Shulan; Wang, Haihe

doi:10.1038/s41388-021-01970-8

Cited by 7 publications

(4 citation statements)

References 39 publications

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“…As an adaptor protein, how Sh3bgrl regulates ECM-and fiber-related genes should be further characterized. It was shown that Sh3bgrl regulates robotic gene expression by binding with various ribosome components in human tumor cells [2,4], which would be confirmed in our zebrafish systems.…”

Section: Discussionsupporting

confidence: 76%

“…SH3BGRL is broadly expressed in many human tissues and organs, including bone marrow, heart, liver, and kidneys [31]. Recently, it is shown that SH3BGRL is associated with some human diseases, including acute myeloid leukemia (AML) [32], neurodegenerative disease [33], and breast cancer [2][3][4]. However, little is known about the relationship between SH3BGRL and female infertility.…”

Section: Discussionmentioning

confidence: 99%

“…However, little is known about its physiological roles in organism development. Recently, our studies showed that SH3BGRL is associated with tumor progression and drug resistance [2][3][4], but these are limited to the cellular level. There is no animal model to dissect the biological function of SH3BGRL during development and diseases.…”

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confidence: 99%

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Loss of the adaptor protein Sh3bgrl initiates ovarian fibrosis in zebrafish

Jin,

Wang,

et al. 2023

FEBS Letters

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Ovarian fibrosis is a reproduction obstacle leading to female infertility in vertebrates, but the cause underlying the cellular events is unclear. Here, we found that the small adaptor protein SH3‐domain‐binding glutamate‐rich protein like (Sh3bgrl) plays an important role in female reproduction in zebrafish. Two sh3bgrl mutant alleles that result in sh3bgrl depletion contribute to female spawning inability. Comparative transcriptome analysis revealed that sh3bgrl knockout mechanistically causes the upregulation of genes associated with extracellular matrix (ECM) and fiber generation in the zebrafish ovary. Consequently, extra ECM or fibers accumulate and are deposited in the ovary, resulting in eventual spawning inability. Our findings thus provide insights into understanding the underlying mechanism of infertility by ovarian fibrosis and provide a novel and valuable model to study female reproduction abnormality.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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Loss of the adaptor protein Sh3bgrl initiates ovarian fibrosis in zebrafish

Jin,

Wang,

et al. 2023

FEBS Letters

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“…UCA1 prolonged the half-life of the PFN1 protein ( Figure 7(a) ). Previous studies have reported that UCA1 regulates ubiquitination-dependent degradation [ 27 , 28 ] and verified the existence of proteasome-dependent PFN1 degradation [ 29 , 30 ]. Hence, we hypothesized that UCA1 might function as a scaffold to recruit ubiquitination-related enzymes and PFN1, further regulating PFN1 ubiquitination-dependent degradation.…”

Section: Resultsmentioning

confidence: 78%

Trophoblast Exosomal UCA1 Induces Endothelial Injury through the PFN1-RhoA/ROCK Pathway in Preeclampsia: A Human-Specific Adaptive Pathogenic Mechanism

Cui

Zhao

et al. 2022

Oxidative Medicine and Cellular Longevity

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Preeclampsia is regarded as an evolution-related disease that has only been observed in humans and our closest relatives, and the important factor contributing to its pathogenesis is endothelial dysregulation secondary to a stressed placenta. Hypoxia-inducible factor 1 subunit alpha (HIF1α), a highly conserved molecule in virtually all mammals, is regarded as a crucial regulator of the hypoxia adaptation and evolution. Persistent high expression of HIF1α in the placenta is one of the pathogenic mechanisms of preeclampsia. Therefore, human-specific molecules should link increased HIF1α to preeclampsia. We reported that urothelial cancer associated 1 (UCA1) is a potential mediator because it is a human-specific long noncoding RNA (lncRNA) that is upregulated in placental tissues and maternal serum from women with preeclampsia and is regulated by HIF1α. The cellular HIF1α-UCA1 pathway promoted the adaptation of trophoblasts to hypoxia by inducing vascular endothelial growth factor (VEGF) secretion and changes in the levels of key enzymes in glycolysis. On the other hand, circulating exosomal UCA1 secreted from stressed trophoblasts induced vascular endothelial dysfunction, especially excess ROS production, as measured by exosome extraction and a coculture system. At the molecular level, UCA1 physically bound to ubiquitin-specific peptidase 14 (USP14), which is a deubiquitinating enzyme, and UCA1 functioned as a scaffold to recruit USP14 to profilin 1 (PFN1), an actin-binding protein contributing to endothelial abnormalities and vascular diseases. This ternary complex inhibited the ubiquitination-dependent degradation of PFN1 and prolonged its half-life, further activating the RhoA/Rho-kinase (ROCK) pathway to induce ROS production in endothelial cells. Taken together, these observations suggest a role for the evolution-related UCA1 in the HIF1α-induced adaptive pathogenic mechanism of preeclampsia, promoting the survival of hypoxic trophoblasts and injuring maternal endothelial cells.

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