Hedgehog signaling is controlled by Rac1 activity

Tang, Chao; Wu, Ximei; Ren, Qianlei; Yao, Minli; Xu, Shouying; Yan, Zhe

doi:10.7150/thno.67702

Cited by 16 publications

(12 citation statements)

References 79 publications

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“…6F ). However, the expression of Gli2, one of the downstream effectors of the Shh pathway [ 38 ], was comparable in the Wdr4 A-cKO and control GNPs (Fig. 6F ).…”

Section: Resultsmentioning

confidence: 99%

“…Even though we did not find out any effector of the Shh/Gli pathway from our proteomic analysis using Wdr4 A-cKO GNPs, we do not exclude the possibility that Wdr4 could impact on the Shh/Gli pathway to control GNP proliferation. Indeed, it was shown that Gli1/2 nuclear translocation in response to Shh requires Rac1 activation, and Rac1 is involved in the progression of Shh-type medulloblastoma [ 38 ]. Since we found that Wdr4 can regulate Rac1 activity (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation

Chiang

Midence

et al. 2023

Cell Death Dis

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Patients with mutations of WDR4, a substrate adaptor of the CUL4 E3 ligase complex, develop cerebellar atrophy and gait phenotypes. However, the underlying mechanisms remain unexplored. Here, we identify a crucial role of Wdr4 in cerebellar development. Wdr4 deficiency in granule neuron progenitors (GNPs) not only reduces foliation and the sizes of external and internal granular layers but also compromises Purkinje neuron organization and the size of the molecular layer, leading to locomotion defects. Mechanistically, Wdr4 supports the proliferation of GNPs by preventing their cell cycle exit. This effect is mediated by Wdr4-induced ubiquitination and degradation of Arhgap17, thereby activating Rac1 to facilitate cell cycle progression. Disease-associated Wdr4 variants, however, cannot provide GNP cell cycle maintenance. Our study identifies Wdr4 as a previously unappreciated participant in cerebellar development and locomotion, providing potential insights into treatment strategies for diseases with WDR4 mutations, such as primordial dwarfism and Galloway-Mowat syndrome.

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“…6F ). However, the expression of Gli2, one of the downstream effectors of the Shh pathway [ 38 ], was comparable in the Wdr4 A-cKO and control GNPs (Fig. 6F ).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation

Chiang

Midence

et al. 2023

Cell Death Dis

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“…We speculated that PC deficiency due to STIL overexpression could inhibit the activated form of SMO and induce the activated form of GLI1 to promote tumorigenesis in bladder cancer. Of note, we observed that GLI1 overexpression mainly located in cytoplasmic in STIL overexpressed cells, suggesting that SHH signalling activation is correlated with the nuclear translocation of GLI1 [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

STIL/AURKA axis promotes cell proliferation by influencing primary cilia formation in bladder cancer

et al. 2023

J Transl Med

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Background The primary cilia (PC) is a microtubule-based and nonmotile organelle which protrudes from the surface of almost all mammalian cells. At present, PC has been found to be a deficiency or loss in multiple cancers. Restoring PC could be a novel targeting therapy strategy. Our research showed that PC was reduced in human bladder cancer (BLCA) cells, and PC deficiency promotes cell proliferation. However, the concrete mechanisms remain unknown. SCL/TAL1 interrupting locus (STIL), a PC-related protein, was screened in our previous study and could influence the cell cycle by regulating PC in tumor cells. In this study, we aimed to elucidate the function of STIL for PC to explore the underlying mechanism of PC in BLCA. Methods Public database analysis, western blot, and enzyme-linked immunosorbent assay (ELISA) were used to screen genes and explore gene expression alteration. Immunofluorescence and western blot were utilized to investigate PC. Wound healing assay, clone formation assay, and CCK-8 assay were used to explore cell migration, growth, and proliferation. The co-immunoprecipitation and western blot were employed to reveal the interaction of STIL and AURKA. Results We found that high STIL expression is correlated with poor outcomes of BLCA patients. Further analysis revealed that STIL overexpression could inhibit PC formation, activate SHH signaling pathways, and promote cell proliferation. In contrast, STIL-knockdown could promote PC formation, inactivate SHH signaling, and inhibit cell proliferation. Furthermore, we found that the regulatory functions of STIL for PC depend on AURKA. STIL could influence proteasome activity and maintain AURKA stabilization. AURKA-knockdown could reverse PC deficiency caused by STIL overexpression for PC in BLCA cells. We observed that co-knockdown in STIL and AURKA significantly enhanced PC assembly. Conclusion In summary, our result provides a potential therapy target for BLCA based on the restoration of PC.

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“…Centchroman (CC), proven to have antitumor activity, prevents β-catenin from entering the cell nucleus to regulate the transcription of migration-related genes by suppressing Rac1/PAK1/β-catenin. As a member of the GEF family, Vav2 can also regulate the activation of Rac1/PAK1 [ 105 ]. It was found that miR-331-3p inhibits Rac1/PAK1/β-catenin by targeting Vav2, thereby inhibiting EMT and the subsequent invasion and migration of tumor cells [ 106 ].…”

Section: Molecular Mechanisms Of Cell Migration Regulated By Rac1mentioning

confidence: 99%

Rac1: A Regulator of Cell Migration and a Potential Target for Cancer Therapy

Luo

et al. 2023

Molecules

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Cell migration is crucial for physiological and pathological processes such as morphogenesis, wound repair, immune response and cancer invasion/metastasis. There are many factors affecting cell migration, and the regulatory mechanisms are complex. Rac1 is a GTP-binding protein with small molecular weight belonging to the Rac subfamily of the Rho GTPase family. As a key molecule in regulating cell migration, Rac1 participates in signal transduction from the external cell to the actin cytoskeleton and promotes the establishment of cell polarity which plays an important role in cancer cell invasion/metastasis. In this review, we firstly introduce the molecular structure and activity regulation of Rac1, and then summarize the role of Rac1 in cancer invasion/metastasis and other physiological processes. We also discuss the regulatory mechanisms of Rac1 in cell migration and highlight it as a potential target in cancer therapy. Finally, the current state as well as the future challenges in this area are considered. Understanding the role and the regulatory mechanism of Rac1 in cell migration can provide fundamental insights into Rac1-related cancer progression and further help us to develop novel intervention strategies for cancer therapy in clinic.

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Hedgehog signaling is controlled by Rac1 activity

Cited by 16 publications

References 79 publications

Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation

Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation

STIL/AURKA axis promotes cell proliferation by influencing primary cilia formation in bladder cancer

Rac1: A Regulator of Cell Migration and a Potential Target for Cancer Therapy

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