Shank-interacting protein–like 1 promotes tumorigenesis via PTEN inhibition in human tumor cells

Abstract

Inactivation of phosphatase and tensin homolog (PTEN) is IntroductionWhile PTEN displays phosphatase activity for both protein and lipid substrates (1), accumulating evidence reveals that its lipid phosphatase activity, which dephosphorylates the 3ʹ-position phosphate from the inositol ring of phosphatidylinositol 3,4,5-triphosphate (PIP 3 ) (2, 3), contributes to PTEN's tumor suppression activities. Thus, PTEN directly antagonizes a critical oncogenic activity mediated by PI3K (4, 5).Consistent with its biochemical functions, inactivation of PTEN is a critical step during tumorigenesis. Typical mechanisms responsible for PTEN inactivation in human cancers include genetic and epigenetic events. The PTEN gene is frequently mutated in human cancers (6-8), including more than 50% of glioblastomas and melanomas, 30%-50% of endometrial carcinomas, and 10% of breast cancers (4, 9, 10). A missense mutation, PTEN/G129E, leading to loss of PTEN's PIP 3 phosphatase activity (4, 11), was detected in Cowden disease (12), a multiple hamartoma syndrome with predisposition to multisystemic malignant tumors (13). Hypermethylation of the PTEN promoter in sporadic colorectal cancers and reduction of PTEN protein without mutations in the PTEN gene in prostate and cervical cancers have also been observed (14-16).Inactivation of PTEN is known to contribute to cervical tumorigenesis. Low levels (2%-16%) of mutations in the PTEN gene as well as the loss of heterozygosity of PTEN have been reported in cervical cancer (17)(18)(19)(20). Consistent with the hypermethylation of PTEN in cervical cancer, reduction in the PTEN protein was observed in approximately 15% of cervical squamous cell carcinomas (21,22). Furthermore, essential pathways that promote cervical tumorigenesis have been shown to inhibit PTEN function. The E6 and E7

miR-338-3p Suppresses Gastric Cancer Progression through a PTEN-AKT Axis by Targeting P-REX2a

“…In addition, RNAi-mediated knockdown or overexpression of P-Rex2a was also able to control xenograft tumor formation in vivo (36). The evidence of cancer xenograft models in our study has already been shown, but studies to date have shown only changes in tumor size when cells were transfected by miR-338-3p and control vector, and then injected to produce the tumor model.…”

Emerging role of SHARPIN in hepatocellular carcinoma progression

“…SHARPIN is also amplified and upregulated in invasive ductal breast cancers [23] . SHARPIN expression was shown to be correlated with Akt activation, consistent with the abovementioned role of SHARPIN in inhibition of PTEN activity [15] . In prostate cancer, upregulated SHARPIN expression induces activation of the NF-κB pathway and its downstream targets Survivin and Livin [24] , which potentially inhibits apoptosis and contributes to tumor development.…”

“…SHARPIN may facilitate tumorigenesis either by interacting with PTEN through its UBL domain to inhibit its phosphatidylinositol 3,4,5-trisphosphate phosphatase activity [15] or by decreasing PTEN expression [16] . SHARPIN also acts as an endogenous inhibitor of integrin signaling [17] .…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…P-Rex2 and SIPL1 bind to PTEN directly and inhibit its lipid phosphatase activity. 64,65 Both of these proteins can stimulate cell growth, at least in part, through their effects on PTEN. P-Rex2a inhibits PTEN lipid phosphatase activity and stimulates the PI3K pathway in the presence of PTEN, whereas knockdown of SIPL1 reduces cell growth in the presence and absence of PTEN, indicating that SIPL1 has other targets besides PTEN.…”