SIPL1-facilitated PTEN ubiquitination contributes to its association with PTEN

Melo, Jason De; Lin, Xiaozeng; He, Lizhi; Wei, Fengxiang; Major, Pierre; Tang, Damu

doi:10.1016/j.cellsig.2014.08.013

Cited by 21 publications

(16 citation statements)

References 40 publications

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“…On the other hand, SHARPIN depletion activates another group of pathways, such as PTEN and p53. The degradation effect of SHARPIN on PTEN was reported in previous study and is also observed in our RNA-seq data [17] (Figure 1 C ). By specific analysis of p53 target genes, we observe that a group of p53 activating target genes is increased, including MDM2, P21 and GADD45A, while the p53 suppressive genes are decreased, such as BCL2 and CCND1.…”

Section: Resultssupporting

confidence: 90%

“…Some breast cancer paper shows that SHARPIN is higher expressed in ER-positive/AKT-positive tumors and promotes breast cancer metastasis [16], [39]. This could be explained that SHARPIN has been shown to bind PTEN and inhibit PTEN function, since PTEN antagonizes AKT activity [17]. Our unpublished data show SHARPIN promotes several oncogenic pathways, including estrogen signaling and AMPK pathway, which might indicates that targeting SHARPIN could be a promising therapeutic strategy by inhibiting several oncogenic pathways.…”

Section: Discussionmentioning

confidence: 74%

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SHARPIN Facilitates p53 Degradation in Breast Cancer Cells

Yang

Wang

et al. 2017

Neoplasia

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The ubiquitin binding protein SHAPRIN is highly expressed in human breast cancer, one of the most frequent female malignancies worldwide. Here, we perform SHARPIN depletion in breast cancer cells together with RNA sequencing. The global expression profiling showed p53 signaling as a potential SHARPIN target. SHARPIN depletion decreased cell proliferation, which effect could be rescue by p53 knocking down. Depletion SHARPIN significantly increases p53 protein level and its target genes in multiple breast cancer cell lines. Further experiment revealed that SHARPIN could facilitate p53 poly-ubiquitination and degradation in MDM2 dependent manner. Immuno-precipitation assay showed that SHARPIN associated with MDM2 and prolonged MDM2 protein stability. Analysis of public available database showed SHARPIN correlated with poor prognosis specifically in p53 wild-type breast cancer patients. Together, our finding revealed a novel modifier for p53/MDM2 complex and suggested SHARPIN as a promising target to restore p53 function in breast cancer.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 74%

SHARPIN Facilitates p53 Degradation in Breast Cancer Cells

Yang

Wang

et al. 2017

Neoplasia

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“…Which of these possibilities is correct and whether filamin regulates other SHARPIN functions remains to be investigated. In another example, SHARPIN enhances PTEN Lys63-linked polyubiquitination, which in turn increases interaction between PTEN and SHARPIN [ 25 ], although it remains unclear what triggers PTEN ubiquitination. At present, whether competition for SHARPIN dictates the balance of these different signaling pathways is unknown as there are no data available on the relevant stoichiometry of SHARPIN and its interacting proteins.…”

Section: Discussionmentioning

confidence: 99%

Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling

et al. 2015

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SHANK-associated RH domain interactor (SHARPIN) inhibits integrins through interaction with the integrin α-subunit. In addition, SHARPIN enhances nuclear factor-kappaB (NF-κB) activity as a component of the linear ubiquitin chain assembly complex (LUBAC). However, it is currently unclear how regulation of these seemingly different roles is coordinated. Here, we show that SHARPIN binds integrin and LUBAC in a mutually exclusive manner. We map the integrin binding site on SHARPIN to the ubiquitin-like (UBL) domain, the same domain implicated in SHARPIN interaction with LUBAC component RNF31 (ring finger protein 31), and identify two SHARPIN residues (V267, L276) required for both integrin and RNF31 regulation. Accordingly, the integrin α-tail is capable of competing with RNF31 for SHARPIN binding in vitro. Importantly, the full SHARPIN RNF31-binding site contains residues (F263A/I272A) that are dispensable for SHARPIN-integrin interaction. Importantly, disrupting SHARPIN interaction with integrin or RNF31 abolishes SHARPIN-mediated regulation of integrin or NF-κB activity, respectively. Altogether these data suggest that the roles of SHARPIN in inhibiting integrin activity and supporting linear ubiquitination are (molecularly) distinct.

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“…5, 6, 7 In addition, Sharpin is reported to bind to tumor suppressor PTEN (phosphatase and tensin homolog) and inhibit its lipid phosphatase activity to promote tumorigenesis. 8, 9 Sharpin also acts as an endogenous inhibitor of integrin signaling to retard cell migration. 10 Furthermore, Sharpin was shown to act as a coactivator for the homeobox protein, SIX homeobox 1 (SIX1), together with eye absent 1 protein (EYA1).…”

Section: Introductionmentioning

confidence: 99%

Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression

et al. 2016

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Sharpin (Shank-associated RH domain-interacting protein, also known as SIPL1) is a multifunctional molecule that participates in various biological settings, including nuclear factor-κB signaling activation and tumor suppressor gene inhibition. Sharpin is upregulated in various types of cancers, including hepatocellular carcinoma (HCC), and is implicated in tumor progression. However, the exact roles of Sharpin in tumorigenesis and tumor progression remain largely unknown. Here we report novel mechanisms of HCC progression through Sharpin overexpression. In our study, Sharpin was upregulated in human HCC tissues. Increased Sharpin expression enhanced hepatoma cell invasion, whereas decrease in Sharpin expression by RNA interference inhibited invasion. Microarray analysis identified that Versican, a chondroitin sulfate proteoglycan that plays crucial roles in tumor progression and invasion, was also upregulated in Sharpin-expressing stable cells. Versican expression increased in the majority of HCC tissues and knocking down of Versican greatly attenuated hepatoma cell invasion. Sharpin expression resulted in a significant induction of Versican transcription synergistically with Wnt/β-catenin pathway activation. Furthermore, Sharpin-overexpressing cells had high tumorigenic properties in vivo. These results demonstrate that Sharpin promotes Versican expression synergistically with the Wnt/β-catenin pathway, potentially contributing to HCC development. A Sharpin/Versican axis could be an attractive therapeutic target for this currently untreatable cancer.

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SIPL1-facilitated PTEN ubiquitination contributes to its association with PTEN

Cited by 21 publications

References 40 publications

SHARPIN Facilitates p53 Degradation in Breast Cancer Cells

SHARPIN Facilitates p53 Degradation in Breast Cancer Cells

Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling

Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression

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