FRAT1, a Substrate-specific Regulator of Glycogen Synthase Kinase-3 Activity, Is a Cellular Substrate of Protein Kinase A

Hagen, Thilo; Cross, Darren A.E.; Culbert, Ainsley A.; West, Andrew B.; Frame, Sheelagh; Morrice, Nick; Reith, Alastair D.

doi:10.1074/jbc.m607003200

Cited by 15 publications

(17 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This included an examination of FRAT1 expression (Hagen et al, 2006;MacDonald et al, 2009;Verheyen and Gottardi, 2010;Bae et al, 2013) and GSK3b phosphorylation (at Ser9 and Tyr216; Wu and Pan, 2010), and an assessment of the expression of CK1 (Stamos and Weis, 2013), PP1 (Stamos and Weis, 2013) and PP2A (Ikeda et al, 2000).…”

Section: Ndrg1 Inhibits B-catenin Phosphorylation At Ser33/37 and Thr41mentioning

confidence: 99%

“…We initially examined the effect of NDRG1 on the GSK3b-binding protein FRAT1, which inhibits the binding of GSK3b to the Axin1-APC-CK1 complex and prevents b-catenin phosphorylation (Thomas et al, 1999;van Amerongen and Berns, 2005;Hagen et al, 2006). For both DU145 and HT29 cells, NDRG1 overexpression significantly upregulated FRAT1 protein (P,0.01) and mRNA (P,0.05 for DU145 cells; P,0.01 for HT29 cells) levels relative to the vector control ( Fig.…”

Section: Ndrg1 Inhibits B-catenin Phosphorylation At Ser33/37 and Thr41mentioning

confidence: 99%

“…FRAT1 prevents GSK3b from binding to the Axin1-APC-CK1 complex by competition with Axin1 for a common or closely overlapping binding site on GSK3b (Fraser et al, 2002). Furthermore, FRAT1 induces GSK3b dissociation from the Axin1-APC-CK1 complex, inhibiting b-catenin phosphorylation and promoting its stabilization (Thomas et al, 1999;van Amerongen and Berns, 2005;Hagen et al, 2006). Increased expression of FRAT1 is correlated with greater cancer cell invasion and metastasis, and poorer patient outcome Guo et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The metastasis suppressor, NDRG1, modulates β-Catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4

Jin¹,

Liu²,

Menezes³

et al. 2014

Journal of Cell Science

123

View full text Add to dashboard Cite

N-myc downstream-regulated gene 1 (NDRG1) is a potent metastasis suppressor that has been demonstrated to inhibit the transforming growth factor b (TGF-b)-induced epithelial-tomesenchymal transition (EMT) by maintaining the cell-membrane localization of E-cadherin and b-catenin in prostate and colon cancer cells. However, the precise molecular mechanism remains unclear. In this investigation, we demonstrate that NDRG1 inhibits the phosphorylation of b-catenin at Ser33/37 and Thr41 and increases the levels of non-phosphorylated b-catenin at the plasma membrane in DU145 prostate cancer cells and HT29 colon cancer cells. The mechanism of inhibiting b-catenin phosphorylation involves the NDRG1-mediated upregulation of the GSK3b-binding protein FRAT1, which prevents the association of GSK3b with the Axin1-APC-CK1 destruction complex and the subsequent phosphorylation of b-catenin. Additionally, NDRG1 is shown to modulate the WNT-b-catenin pathway by inhibiting the nuclear translocation of b-catenin. This is mediated through an NDRG1-dependent reduction in the nuclear localization of p21-activated kinase 4 (PAK4), which is known to act as a transporter for b-catenin nuclear translocation. The current study is the first to elucidate a unique molecular mechanism involved in the NDRG1-dependent regulation of b-catenin phosphorylation and distribution.

show abstract

Section: Ndrg1 Inhibits B-catenin Phosphorylation At Ser33/37 and Thr41mentioning

confidence: 99%

Section: Ndrg1 Inhibits B-catenin Phosphorylation At Ser33/37 and Thr41mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The metastasis suppressor, NDRG1, modulates β-Catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4

Jin¹,

Liu²,

Menezes³

et al. 2014

Journal of Cell Science

123

View full text Add to dashboard Cite

show abstract

“…Frat1, a member of the Frat (Frequently rearranged in advanced T-cell lymphomas) family, has been considered to be an activator in the Wnt signal transduction pathway [1,2] and has been noted to be overexpressed in human esophageal squamous cell carcinomas [3] and ovarian cancers [4]. The expression of Frat1 is considered to be crucial for the maintenance of the malignant cellular phenotype.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Frat1 correlates with malignant phenotype and advanced stage in human non-small cell lung cancer

Zhang

Lin

et al. 2011

Virchows Arch

View full text Add to dashboard Cite

Frat1 has been reported to be overexpressed in several human malignant tumors, including esophageal squamous, cervical, breast, and ovarian carcinoma, but the role of Frat1 in lung cancer is unknown. Our purpose is to investigate the expression of Frat1 and its correlation with clinicopathologic features and prognosis in lung cancer patients. Immunohistochemistry was performed on 137 cases of non-small cell lung cancer (NSCLC), including 78 cases with clinical follow-up, and Western blot and reverse transcription-polymerase chain reaction (RT-PCR) assays were performed to detect the protein and mRNA expression levels in 30 NSCLC and autologous matched normal tissues. In addition, lung cancer cell line A549 was transfected with Frat1-siRNA plasmids and Matrigel invasive assay was carried out to study the function of Frat1 in cancer cell invasiveness. The results showed that Frat1 was expressed in 85 (62.04%) cases of NSCLC by immunohistochemistry, while all 30 specimens of normal lung tissues were negative. Western blot and RT-PCR results for Frat1 mRNA were in agreement with immunohistochemical findings. Of interest, the expression of Frat1 was strongly correlated with tumor differentiation, TNM stage, and lymph node metastasis (P < 0.05). The Kaplan-Meier survival analysis demonstrated that the cases with Frat1 expression had significantly shorter survival than those without Frat1 (P < 0.001). In addition, down-regulation of Frat1 expression reduced the invasive ability in the A549 cell line, further supporting the idea that Frat1 may play a crucial role in carcinogenesis, tumor invasiveness and dissemination in human lung cancer.

show abstract

“…FRAT1 (frequently rearranged in advanced T-cell lymphomas-1) gene is located on human chromosome 10q24.1 [4], encoding a 29-kDa protein comprising 279 amino acids. FRAT1 (also named GBP for GSK-3-binding protein) was first identified in Xenopus as a protein that inhibits glycogen synthase kinase-3 (GSK-3) in vivo, appearing to act as a positive regulator of the Wnt signaling pathway by stabilizing b-catenin [5][6][7]. Recently, there are some supportive reports showing that FRAT1 also plays a role in tumor progression [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

FRAT1 expression and its correlation with pathologic grade, proliferation, and apoptosis in human astrocytomas

et al. 2009

View full text Add to dashboard Cite

FRAT1 was originally characterized as a protein frequently rearranged in advanced T-cell lymphoma, which inhibits GSK-3-mediated phosphorylation of β-catenin and positively regulates the Wnt signaling pathway. FRAT1 has recently been identified as a proto-oncogene involved in tumorigenesis, as elevated expression of FRAT1 was detected in several types of human cancers. However, the relationship between FRAT1 and human astrocytomas is unclear. In this study, we detected the expression of FRAT1 in 76 patients with human astrocytoma by immunohistochemistry. The proliferative index (PI) of tumor cells was evaluated by Ki-67 staining, and the apoptotic index (AI) was determined by fluorometric TdT-mediated dUTP nick end labeling (TUNEL) assay. The results showed that the FRAT1 immunoreactivity score (IRS), PI, and AI of astrocytoma were 4.11 ± 3.86, 31.92 ± 20.00%, and 2.66 ± 1.66%, respectively, and all of them increased markedly with the increase of pathologic grade of astrocytomas (P < 0.001 for all). The PI in the FRAT1-positive group was significantly higher than that in the FRAT1-negative group (P < 0.001). In addition, the PI was positively correlated with FRAT1 IRS (P < 0.001). Although there was no significant difference between the AI in the FRAT1-positive group and that in the FRAT1-negative group (P = 0.123), the AI was inversely correlated with FRAT1 IRS (P = 0.022). In conclusion, FRAT1 may be an important factor in the tumorigenesis and progression of astrocytoma, which could be used as a potential biomarker for pathological diagnosis of malignancy and a target for biological therapy.

show abstract

FRAT1, a Substrate-specific Regulator of Glycogen Synthase Kinase-3 Activity, Is a Cellular Substrate of Protein Kinase A

Cited by 15 publications

References 40 publications

The metastasis suppressor, NDRG1, modulates β-Catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4

The metastasis suppressor, NDRG1, modulates β-Catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4

Overexpression of Frat1 correlates with malignant phenotype and advanced stage in human non-small cell lung cancer

FRAT1 expression and its correlation with pathologic grade, proliferation, and apoptosis in human astrocytomas

Contact Info

Product

Resources

About