RagA, an mTORC1 activator, interacts with a hedgehog signaling protein, WDR35/IFT121

Sekiguchi, Toshio; Furuno, Nobuaki; Ishii, Takashi; Hirose, Eiji; Sekiguchi, Fumiko; Wang, Yonggang; Kobayashi, Hideki

doi:10.1111/gtc.12663

Cited by 5 publications

(4 citation statements)

References 46 publications

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“…Despite that RAGA is well recognized to activate mTORC1 by recruiting mTORC1 complex to the lysosome, some studies have demonstrated that RAGA might also play functions other than mTORC1 through various interaction proteins such as nucleolar protein NG132 26 , microtubule cargo adapter DYLNT 27 , and hedgehog signaling protein WDR35 28 . In this study, we identify CD47 as a new RAGA interaction protein and RAGA promotes CD47 lysosome degradation in a mTORC1-independent manner.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to activate amino acid-dependent mTORC1, emerging evidences have demonstrated that RAGA can also function independently of mTORC1. Some studies have demonstrated that RAGA may play functions other than mTORC1 through various interaction proteins such as nucleolar protein NG132 26 , microtubule cargo adapter DYLNT 27 , and hedgehog signaling protein WDR35 28 . Interestingly, it has been reported that RAGA expresses in microglia, the resident macrophage in the central nervous system, and is essential for the cell development and function of microglia.…”

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confidence: 99%

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RAGA prevents tumor immune evasion of LUAD by promoting CD47 lysosome degradation

Zheng

Zhen

et al. 2023

Commun Biol

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CD47 is a macrophage-specific immune checkpoint protein acting by inhibiting phagocytosis. However, the underlying mechanism maintaining CD47 protein stability in cancer is not clear. Here we show that CD47 undergoes degradation via endocytosis/lysosome pathway. The lysosome protein RAGA interacts with and promotes CD47 lysosome localization and degradation. Disruption of RAGA blocks CD47 degradation, leading to CD47 accumulation, high plasma membrane/intracellular CD47 expression ratio and reduced phagocytic clearance of cancer cells. RAGA deficiency promotes tumor growth due to the accumulation of CD47, which sensitizes the tumor to CD47 blockade. Clinical analysis shows that RAGA and CD47 proteins are negatively correlated in lung adenocarcinoma patient samples. High RAGA protein level is related to longer patient survival. In addition, RAGAhighCD47low patients show the longest overall survival. Our study thereby not only reveals a mechanism by which RAGA regulates CD47 lysosome degradation, but also suggests RAGA is a potential diagnostic biomarker of lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

RAGA prevents tumor immune evasion of LUAD by promoting CD47 lysosome degradation

Zheng

Zhen

et al. 2023

Commun Biol

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“…The SNP rs721932 lies in the first intron of AC079145.1 and about 1kb upstream of WDR35. The WDR35 gene, encoding a WD‐repeat protein, has been reported to be requisite for ciliary function, which plays a vital role in the transduction of signals in the hedgehog pathway 23‐26 . Recent studies have shown that this pathway was unveiled to participate in cardiovascular phenotypes, such as myocardial ischemia 27 .…”

Section: Discussionmentioning

confidence: 99%

Association study of genetic variants at TTC32‐WDR35 gene cluster with coronary artery disease in Chinese Han population

Yang

et al. 2020

Clinical Laboratory Analysis

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Background TTC32‐WDR35 gene cluster has been genome‐wide significantly associated with coronary artery disease (CAD). However, the common variants in this region contributing to CAD risk remain elusive. Methods We performed a case‐control study enrolling 935 CAD cases and 935 age‐sex‐frequency‐matched controls from unrelated southwest Chinese Han population. Five variants were determined by TaqMan assay. Results This study indicated that rs721932 CG genotype was associated with CAD risk (OR = 0.68, 95% CI: 0.54‐0.86; P = .001). Stratified analysis showed that the risk associated with rs12617744 AA genotype was robust in male (OR = 0.62, 95% CI: 0.42‐0.93, P = .02). The gene dosage of the risk allele at rs12617744 showed a significant association with left circumflex artery disease (P = .027) and the number of vascular lesions in patients (P = .034). Moreover, the gene dosage of rs721932 risk allele was associated with vascular lesion numbers (P = .048) and the progression of CAD (P = .028). Compared with carriers of major alleles, the AA genotype of rs12617744 and GG genotype of rs721932 were both associated with plasma HDL level (P = .009 and 0.004, respectively). Expression quantitative trait locus (eQTL) results showed significantly different TTC32 expression of subjects as a function of SNPs (rs2278528, rs7594214, and rs721932) genotype in the artery. Besides, FPRP analysis did support the strong links between polymorphisms and CAD risk. Conclusions SNP rs721932 at TTC32‐WDR35 Gene Cluster was associated with CAD risk, and rs12617744 was associated with the risk of CAD among males. Both SNPs may contribute to the regulation of plasma HDL levels and possibly to the severity of CAD in Chinese Han population.

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“…However, the interaction between RagA and WDR35 seemed to be located at the ER and not at the lysosomes. Thus, this possible dual regulation might be mediated through subcellular translocation of proteins involved in both Hh and mTORC1 signaling, in a manner mediated by RagA and WDR35 interactions [ 137 ].…”

Section: Mechanisms Leading To Hh/mtor Crosstalkmentioning

confidence: 99%

Crosstalk of Hedgehog and mTORC1 Pathways

Larsen

Møller

2020

Cells

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Hedgehog (Hh) signaling and mTOR signaling, essential for embryonic development and cellular metabolism, are both coordinated by the primary cilium. Observations from cancer cells strongly indicate crosstalk between Hh and mTOR signaling. This hypothesis is supported by several studies: Evidence points to a TGFβ-mediated crosstalk; Increased PI3K/AKT/mTOR activity leads to increased Hh signaling through regulation of the GLI transcription factors; increased Hh signaling regulates mTORC1 activity positively by upregulating NKX2.2, leading to downregulation of negative mTOR regulators; GSK3 and AMPK are, as members of both signaling pathways, potentially important links between Hh and mTORC1 signaling; The kinase DYRK2 regulates Hh positively and mTORC1 signaling negatively. In contrast, both positive and negative regulation of Hh has been observed for DYRK1A and DYRK1B, which both regulate mTORC1 signaling positively. Based on crosstalk observed between cilia, Hh, and mTORC1, we suggest that the interaction between Hh and mTORC1 is more widespread than it appears from our current knowledge. Although many studies focusing on crosstalk have been carried out, contradictory observations appear and the interplay involving multiple partners is far from solved.

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RagA, an mTORC1 activator, interacts with a hedgehog signaling protein, WDR35/IFT121

Cited by 5 publications

References 46 publications

RAGA prevents tumor immune evasion of LUAD by promoting CD47 lysosome degradation

RAGA prevents tumor immune evasion of LUAD by promoting CD47 lysosome degradation

Association study of genetic variants at TTC32‐WDR35 gene cluster with coronary artery disease in Chinese Han population

Crosstalk of Hedgehog and mTORC1 Pathways

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