Dual functions of Rack1 in regulating Hedgehog pathway

Li, Yan; Sun, Xuxu; Gao, Dongqing; Ding, Yan; Liu, Jinxiao; Chen, Jiong; Luo, Jun; Zhang, Junzheng; Liu, Qingxin; Zhou, Zizhang

doi:10.1038/s41418-020-0563-7

Cited by 13 publications

(11 citation statements)

References 56 publications

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“…55 SMO is a crucial receptor essential for the activation of Hedgehog pathway. 56 Our findings indicate that the expression of SMO was notably increased in the kidney tissues of patients and rats with DN. Correlation analysis revealed a high correlation between SMO and EMT in kidneys of rats.…”

Section: Kidney Smo Expression Tracks With Emt In Dn Patientsmentioning

confidence: 53%

Human umbilical cord mesenchymal stem cell‐derived exosomes ameliorate renal fibrosis in diabetic nephropathy by targeting Hedgehog/SMO signaling

Zhang,

Zheng,

et al. 2024

The FASEB Journal

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Diabetic nephropathy (DN) is the leading cause of end‐stage renal disease globally. Currently, there are no effective drugs for the treatment of DN. Although several studies have reported the therapeutic potential of mesenchymal stem cells, the underlying mechanisms remain largely unknown. Here, we report that both human umbilical cord MSCs (UC‐MSCs) and UC‐MSC‐derived exosomes (UC‐MSC‐exo) attenuate kidney damage, and inhibit epithelial‐mesenchymal transition (EMT) and renal fibrosis in streptozotocin‐induced DN rats. Strikingly, the Hedgehog receptor, smoothened (SMO), was significantly upregulated in the kidney tissues of DN patients and rats, and positively correlated with EMT and renal fibrosis. UC‐MSC and UC‐MSC‐exo treatment resulted in decrease of SMO expression. In vitro co‐culture experiments revealed that UC‐MSC‐exo reduced EMT of tubular epithelial cells through inhibiting Hedgehog/SMO pathway. Collectively, UC‐MSCs inhibit EMT and renal fibrosis by delivering exosomes and targeting Hedgehog/SMO signaling, suggesting that UC‐MSCs and their exosomes are novel anti‐fibrotic therapeutics for treating DN.

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Section: Kidney Smo Expression Tracks With Emt In Dn Patientsmentioning

confidence: 53%

Human umbilical cord mesenchymal stem cell‐derived exosomes ameliorate renal fibrosis in diabetic nephropathy by targeting Hedgehog/SMO signaling

Zhang,

Zheng,

et al. 2024

The FASEB Journal

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“…RACK1, ubiquitously expressed in a wide range of tissues, was initially identified as an anchoring protein for protein kinase C (55). With an increasing number of reports showing its interaction with a large number of signaling transduction complexes and signaling pathways, such as Src family kinases, HIF-1, the Hedgehog pathway, the AKT pathway and the NF-kB pathway, RACK1 has been widely perceived as a platform for integrating diverse signaling activities (50)(51)(52)(53)(54)(56)(57)(58)(59). The NF-kB pathway was also significantly enriched in CCDC102Boverexpressing breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Stabilization of CCDC102B by Loss of RACK1 Through the CMA Pathway Promotes Breast Cancer Metastasis via Activation of the NF-κB Pathway

Guo

Xiu

et al. 2022

Front. Oncol.

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BackgroundBreast cancer is one of the leading causes of cancer-related death among women, and the pathological status of axillary lymph nodes is an important predictor of prognosis. However, the mechanism involved in this early stage of metastasis remains largely unknown.MethodsMicroarray analysis was used to carry out differential genomics analyses between matched pairs of metastatic sentinel lymph node tissues and breast primary tumors. The CRISPR/Cas9 gene editing system was used for in vivo screening by transplanting a loss-of-function cell pool into immunocompromised mice. MAGeCK was used to analyze the screening results. Survival analysis was performed via the Kaplan–Meier method. Cell proliferation, wound healing, migration and invasion assays were performed to confirm the phenotype. A tail vein model and subcutaneous xenotransplanted tumor model were used for the in vivo study. The relationship between coiled-coil domain containing 102B (CCDC102B) and receptor for activated C kinase 1 (RACK1) was examined using coimmunoprecipitation, mass spectrometry, nuclear protein extraction and immunofluorescence assays. The primary biological functions and pathways related to CCDC102B were enriched by RNA sequencing.ResultsWe identified CCDC102B through screening and found that it was significantly upregulated in metastatic lesions in lymph nodes compared to matched primary tumors. Increased expression of CCDC102B promoted breast cancer metastasis in vitro and in vivo. Additionally, high expression of CCDC102B was correlated with poor clinical outcomes in breast cancer patients. We further identified that CCDC102B was stabilized by the loss of RACK1, a protein negatively correlated with breast cancer metastasis. Mechanistically, we found that RACK1 promoted CCDC102B lysosomal degradation by mediating chaperone-mediated autophagy (CMA). The aggressive behavior of CCDC102B in breast cancer cells could be reversed by the expression of RACK1. Moreover, CCDC102B was correlated with the significant enrichment of NF-κB pathway components. Overexpressing CCDC102B led to less interaction between RACK1 and IKKa. Thus, CCDC102B positively regulates the NF−κB pathway by interacting with RACK1.ConclusionTaken together, our findings uncover a novel role of CCDC102B in breast cancer metastasis. CCDC102B serves as a potential metastasis promoter by regulating the activation of the NF-κB pathway and can be degraded by RACK1 via CMA.

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“…The ptc-gal4 , Ay-gal4 , mirr-gal4 , UAS-GFP had been described in our previous studies [ 38 , 39 ]. UAS-Fg -usp8 and usp8 -RNAi (#5798R-1, NIG; #107623, VDRC) were kindly provided from Dr. Junzheng Zhang’s lab [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

“…The protein stability assay was conducted as previously described [ 39 ]. In brief, 293 T cells were plated in the cell dishes (10 cm) and transfected with indicated plasmids.…”

Section: Methodsmentioning

confidence: 99%

Usp8 promotes tumor cell migration through activating the JNK pathway

et al. 2022

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Tumor metastasis is the most cause of high mortality for cancer patients. Identification of novel factors that modulate tumor cell migration is of great significance for therapeutic strategies. Here, we find that the ubiquitin-specific protease 8 (Usp8) promotes tumor cell migration through activating the c-Jun N-terminal kinase (JNK) pathway. Genetic epistasis analyses uncover Usp8 acts upstream of Tak1 to control the JNK pathway. Consistently, biochemical results reveal that Usp8 binds Tak1 to remove ubiquitin modification from Tak1, leading to its stabilization. In addition, human USP8 also triggers tumor cell migration and activates the JNK pathway. Finally, we show that knockdown of USP8 in human breast cancer cells suppresses cell migration. Taken together, our findings demonstrate that a conserved Usp8-Tak1-JNK axis promotes tumor cell migration, and providing USP8 as a potential therapeutic target for cancer treatment.

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Dual functions of Rack1 in regulating Hedgehog pathway

Cited by 13 publications

References 56 publications

Human umbilical cord mesenchymal stem cell‐derived exosomes ameliorate renal fibrosis in diabetic nephropathy by targeting Hedgehog/SMO signaling

Human umbilical cord mesenchymal stem cell‐derived exosomes ameliorate renal fibrosis in diabetic nephropathy by targeting Hedgehog/SMO signaling

Stabilization of CCDC102B by Loss of RACK1 Through the CMA Pathway Promotes Breast Cancer Metastasis via Activation of the NF-κB Pathway

Usp8 promotes tumor cell migration through activating the JNK pathway

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