Shank-associated RH domain interactor signaling in tumorigenesis

Abstract

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.

Keywords: LUBAC; PRMT5; PTEN; SHARPIN; p53; tumorigenesis.

Figure 1.

Historical process of resolving SHARPIN function. SHARPIN was originally identified in the PSD of mice, functioning in the nervous system. SHARPIN is reported to participate in inflammatory-associated diseases and tumors. Researchers gradually realized that SHARPIN is a novel component of the LUBAC and mediates the NF-κB signaling pathway. Subsequently, SHARPIN-mediated regulation of p53, PRMT5, Rap1 and PTEN signaling in tumors has been reported. SHARPIN, shank-associated RH domain interactor; PSD, postsynaptic density; LUBAC, linear ubiquitin chain assembly complex; PRMT5, protein arginine methyltransferase 5; PTEN, phosphatase and tensin homolog, Rap1, ras-associated protein-1.

Figure 2.

Difference between SHARPIN presence and absence in regulating the NF-κB signaling pathway. (A) Presence of SHARPIN promotes canonical NF-κB signaling activation. Once stimulators bind with the receptors, associated molecules are recruited to activate the IKK complex. The complete LUBAC is involved in this process that serves a role in ubiquitination and fully activates the IKK complex. Subsequently, the phosphorylation and ubiquitination of IKBα contributes to the degradation of IKBα, which generates dimers. The dimers translocate into the nucleus and mediate target gene transcription. (B) Absence of SHARPIN attenuates canonical NF-κB signaling activation. When SHARPIN is absent, the LUBAC attenuates the phosphorylation and ubiquitination of IKBα, resulting in reduced IKBα degradation and inhibiting dimer translocation into the nucleus. Therefore, transcription of the target genes is inhibited. SHARPIN, shank-associated RH domain interactor; IKK, inhibition of κB kinase; LUBAC, linear ubiquitin chain assembly complex; TNF, tumor necrosis factor; TNFR1, TNF receptor 1; TRADD, TNFR type 1-associated DEATH domain protein; TRAF2, TNFR-associated factor 2; RIP1, receptor-interacting serine/threonine protein kinase 1; cIAP1/2, cellular inhibitor of apoptosis protein-1/2; FADD, FAS-associated death domain protein; HOIL-1L, heme-oxidized IRP2 ligase 1L; HOIP, HOIL-1 interacting protein; NEMO, NF-κB essential modulator; p, phosphorylated; Ub, ubiquitinated.

Figure 3.

SHARPIN regulates multiple signaling pathways in tumorigenesis. A: SHARPIN mediates p53 ubiquitination and rapid degradation by the proteasome, which promotes tumorigenesis. B: SHARPIN interacts with PRMT5 and activates SOX10, PAX3 and MITF, which promotes tumorigenesis. PRMT5 also regulates PAX3 and MITF and inhibits p53 in tumorigenesis. C: SHARPIN upregulates Rap, which promotes melanoma development through p38 and JNK/c-Jun signaling. D: SHARPIN can bind with PTEN, which mediates tumorigenesis through the PI3K/AKT signaling pathway. SOX10, SRY-box transcription factor 10; MITF, melanocyte inducing transcription factor; PAX3, paired box 3; PRMT5, protein arginine methyltransferase 5; SHARPIN, shank-associated RH domain interactor; Rap1, ras-associated protein 1; JNK, c-Jun N-terminal kinases; MDM2, mouse double minute 2 homolog; PTEN, phosphatase and tensin homologue deleted on chromosome 10; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PIP2, phosphatidylinositol (4,5)-bisphosphate; PI3K, phosphoinositide 3-kinases; p, phosphorylated; Ub, ubiquitinated.