SHARPIN Promotes Melanoma Progression via Rap1 Signaling Pathway

Zhou, Sitong; Liang, Yanhua; Zhang, Xi; Liao, Lexi; Yao, Yang; Ouyang, Wen; Xu, Huaiyuan

doi:10.1016/j.jid.2019.07.696

Cited by 39 publications

(30 citation statements)

References 59 publications

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“…The functional implications and regulatory mechanisms of SHARPIN need to be explored in detail in both on an immunological basis and therapeutic basis. SHARPIN has been highly explored in many disease conditions, especially in cancer stressing out its multiple roles in many LUBAC-independent regulatory mechanisms [28, 29], suggesting that this modification that we have identified, if not targeted for a proteosomal degradation, might be inhibiting only the LUBAC-dependent SHARPIN function, promoting its other cellular functions, which is out of scope for this study.…”

Section: Discussionmentioning

confidence: 99%

A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer’s disease

Krishnan

Menon

et al. 2019

Preprint

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23 INTRODUCTION: Defective immune cell-mediated clearance of amyloid-beta (Aβ) and 24 Aβ-associated inflammatory activation of immune cells are key contributors of Aβ 25 accumulation and neurodegeneration in Alzheimer's disease (AD), however, the underlying 26 mechanisms remain elusive. 27 METHODS: Differentiated THP-1 cells treated with Aβ and AD patient-derived 28 macrophages were used as in-vitro model. The role of SHARPIN was analysed in 29 differentiated THP-1 cells using siRNA-mediated knockdown followed by immunoblotting, 30 ELISA, real-time PCR, immunoprecipitation and flow cytometry. Differentiated SHSY5Y 31cells were used to study inflammation-mediated apoptosis. 32RESULTS: SHARPIN was found to regulate Aβphagocytosis and NLRP3 expression in 33 THP-1 derived macrophages. Further, it was found to promote macrophage polarization to an 34 M1 (pro-inflammatory) phenotype resulting in enhanced inflammation and associated 35 neuronal death, demonstrated using in-vitro culture systems. SHARPIN expression by blood-36 derived macrophages was further found to be higher in the early stages of AD, which 37 correlates with Aβ 40/42 concentration in the plasma and age of the study subjects. 38DISCUSSION: The novel protein, SHARPIN has been shown to play critical roles in 39 regulation of Aβ-phagocytosis and inflammation in AD and the mechanism by which 40 SHARPIN is activated by Aβ in macrophages has been elucidated. 41 42 Keywords: SHARPIN, amyloid-beta, Alzheimer's disease, mild cognitive impairment, 43 macrophage, NLRP3, inflammation, phagocytosis, oxidative stress. 44 3 Abbreviations: AD, Alzheimer's disease; Aβ, amyloid-beta; MCI, Mild Cognitive 45 Impairment; SHARPIN, Shank-associated RH domain-interacting protein; NLRP3, 46 nucleotide-binding domain (NOD)-like receptor protein 3; ASC, Apoptosis-associated Speck-47 like protein containing a caspase-recruitment domain (CARD); LUBAC, linear 48 ubiquitination assembly complex; iNOS, induced Nitric Oxide Synthase; IL-1β, Interleukin-49 1beta; TGF-β, Transforming Growth Factor-1beta; TNF-α, Tumor Necrosis Factor-alpha; 50 PBMC, Peripheral Blood Mononuclear cells; NF-κB, Nuclear Factor kappa-light chain-51 enhancer of activated B cells; ROS, reactive oxygen species; CRP, C-Reactive Protein; PBS, 52 Phosphate-buffered saline; RPMI, Roswell Park Memorial Institute; FBS, fetal bovine 53 serum; THP-1, Tohoku Hospital Pediatrics-1; NH 4 OH, Ammonium hydroxide; FITC, 54 Fluorescein isothiocyanate. 55 56 57 58 59 60 61 62 63 64 4 polarization to M1 (pro-inflammatory) phenotype in differentiated THP-1 cell line as an in-89 vitro model and SHARPIN silencing protects neurons from Aβ-induced inflammatory 90 damage using differentiated SHSY5Y cell line. Further, utilizing control, mild cognitively 91 impaired (MCI) and AD patient-derived macrophages, we show that SHARPIN plays a 92 significant role the progression of AD. 93 2. Materials and methods 94 2.1. Inclusion of study subjects 95 AD and MCI patients were recruited from the Memory & Neurobehavioral Clinic (MNC) at 96 the S...

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Section: Discussionmentioning

confidence: 99%

A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer’s disease

Krishnan

Menon

et al. 2019

Preprint

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“…This finding suggests that SHARPIN and Rap1 functions may be closely associated. Furthermore, a recent study also supported this viewpoint, demonstrating that SHARPIN promotes melanoma progression through Rap1 via the p38 and JNK/Jun signaling pathways (18) (Fig. 3).…”

Section: Sharpin Interacts With Rap1 In Tumorigenesismentioning

confidence: 54%

“…Additionally, it has been reported that SHARPIN interaction with protein arginine methyltransferase 5 (PRMT5) mediates tumor cell growth ( 3 ). Notably, Zhou et al ( 18 ) demonstrated that SHARPIN upregulates ras-associated protein-1 (Rap1), which promotes melanoma development through p38 and c-Jun N-terminal kinases (JNK)/c-Jun signaling pathways. A previous study also revealed that SHARPIN mediates the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) signaling pathway, which promotes tumorigenesis by phosphoinositide 3-kinase (PI3K)/AKT signaling ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

Shank‑associated RH domain interactor signaling in tumorigenesis (Review)

et al. 2020

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Shank-associated RH domain interactor (SHARPIN) is a component of the linear ubiquitin chain activation complex, which is essential for p53 signaling and inflammation. Previous studies have demonstrated that SHARPIN functions in tumor cell survival, growth, invasion and tumorigenesis. These functions include the regulation of p53 proteins via poly-ubiquitination, interaction with a type II protein arginine methyltransferase 5 in melanoma cells, modulating ras-associated protein-1 through p38 and c-Jun N-terminal kinases/c-Jun signaling, and mediating phosphoinositide 3-kinase/AKT signaling via phosphatase and tensin homologue deleted on chromosome 10. Hence, SHARPIN not only participates in the inflammatory response but also serves a critical role in tumor cells. The present review summarizes the biological functions of the absence or presence of SHARPIN with regard to activating the canonical NF-κB signaling pathway and the effects on p53 and other signaling pathways for the modulation of tumorigenesis. Therefore, this review provides insight into the underlying role and mechanisms of SHARPIN in tumorigenesis, as well as its potential application in cancer therapy.

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“…RAL was described as an inducer of proliferation in melanoma cell lines, even in the presence of NRAS and/or BRAF oncogenic mutations (Mishra et al, 2010;Zipfel et al, 2010) (Table 1). Likewise, RAP1 is upregulated in melanoma cell lines and mediates melanoma cell proliferation and invasion, contributing to resistance to MAPK inhibitors (Hernández-Varas et al, 2011;Rodríguez et al, 2017;Zhou et al, 2020) (Table 1). Moreover, RAP1 inhibition reduces melanoma cell adhesion and migration by suppressing tumor cell extravasation and consequently lung colonization in in vivo models (Freeman et al, 2010).…”

Section: Ras Family Members Involved In Melanoma Growth Aggressivenementioning

confidence: 99%

Subversion of Ras Small GTPases in Cutaneous Melanoma Aggressiveness

Brito¹,

Barral

Pojo³

2020

Front. Cell Dev. Biol.

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The rising incidence and mortality rate associated with the metastatic ability of cutaneous melanoma represent a major public health concern. Cutaneous melanoma is one of the most invasive human cancers, but the molecular mechanisms are poorly understood. Moreover, currently available therapies are not efficient in avoiding melanoma lethality. In this context, new biomarkers of prognosis, metastasis, and response to therapy are necessary to better predict the disease outcome. Additionally, the knowledge about the molecular alterations and dysregulated pathways involved in melanoma metastasis may provide new therapeutic targets. Members of the Ras superfamily of small GTPases regulate various essential cellular activities, from signaling to membrane traffic and cytoskeleton dynamics. Therefore, it is not surprising that they are differentially expressed, and their functions subverted in several types of cancer, including melanoma. Indeed, Ras small GTPases were found to regulate melanoma progression and invasion. Hence, a better understanding of the mechanisms regulated by Ras small GTPases that are involved in melanoma tumorigenesis and progression may provide new therapeutic strategies to block these processes. Here, we review the current knowledge on the role of Ras small GTPases in melanoma aggressiveness and the molecular mechanisms involved. Furthermore, we summarize the known involvement of these proteins in melanoma metastasis and how these players influence the response to therapy.

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SHARPIN Promotes Melanoma Progression via Rap1 Signaling Pathway

Cited by 39 publications

References 59 publications

A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer’s disease

A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer’s disease

Shank‑associated RH domain interactor signaling in tumorigenesis (Review)

Subversion of Ras Small GTPases in Cutaneous Melanoma Aggressiveness

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