PTPN14 Forms a Complex with Kibra and LATS1 Proteins and Negatively Regulates the YAP Oncogenic Function

Wilson, Kayla E.; Li, Yingwei; Yang, Nuo; Shen, He; Orillion, Ashley; Zhang, Jianmin

doi:10.1074/jbc.m113.534701

Cited by 79 publications

(96 citation statements)

References 40 publications

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“…Ptpn14 interacts with multiple proteins, such as β-Catenin (Wadham et al, 2003) and p130Cas (Zhang et al, 2013), but its best-characterized binding partner is Yap, a transcriptional coactivator and component of the Hippo growth regulatory pathway (Huang et al, 2013; Liu et al, 2013; Michaloglou et al, 2013; Wang et al, 2012; Wilson et al, 2014). Ptpn14 also interacts with Kibra and Lats1, other Hippo pathway components that negatively regulate Yap (Poernbacher et al, 2012; Wilson et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

et al. 2017

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SUMMARY The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p5353,54 TAD2 mutant behaves as a “super-tumor suppressor”, with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression.

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Section: Resultsmentioning

confidence: 99%

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

et al. 2017

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“…Furthermore, RT-qPCR and Western blot analyses showed that mRNA and protein levels of PTPN14 and PTEN were dramatically upregulated in HUCCT1 and RBE cells when miR-21 expression was inhibited (Figure 3D, Figure 3E, Figure 3F). We also investigated the effect of miR-21 on Yes-associated protein 1 (YAP) which has been demonstrated to be directly regulated by PTPN14 [35, 36] and Akt which was the downstream of PTEN. As anticipated, the expression of YAP, and pAkt was significantly downregulated in HUCCT1 and RBE cells when miR-21 expression was inhibited (Figure 3E and Figure 3F).…”

Section: Resultsmentioning

confidence: 99%

MiR-21 promotes intrahepatic cholangiocarcinoma proliferation and growth in vitro and in vivo by targeting PTPN14 and PTEN

Wang

Sui

et al. 2015

Oncotarget

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Intrahepatic cholangiocarcinoma (ICC) constitutes the second-most common primary hepatic malignancy. MicroRNAs (miRNAs) play important roles in the pathogenesis of ICC. However, the clinical significance of miR-21 levels in ICC remains unclear. Here, we investigated the role of miR-21 in ICC and found that its expression was significantly upregulated in serum of ICC patients. Serum miR-21 levels robustly distinguished ICC patients from control subjects. Further experiments showed that inhibition of miR-21 suppressed ICC cell proliferation in vitro and tumor growth in vivo. Specifically, inhibition of miR-21 induced cell cycle arrest and apoptosis. Moreover, PTPN14 and PTEN were identified as direct and functional targets of miR-21. Finally, we showed high expression levels of miR-21 were closely related to adverse clinical features, diminished survival, and poor prognosis in ICC patients. This study revealed functional and mechanistic links between miR-21 and tumor suppressor genes, PTPN14 and PTEN, in the pathogenesis of ICC. MiR-21 not only plays important roles in the regulation of cell proliferation and tumor growth in ICC, but is also a diagnostic and prognostic marker, and a potential therapeutic target for ICC.

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“…Alongside these characterized functions in Hippo signaling, recent studies have revealed a role for KIBRA in cell migration and polarization (43)(44)(45). Overexpression of KIBRA can inhibit migration of MCF10A cells (44). In contrast, KIBRA knockdown in breast cancer cells induced the epithelialto-mesenchymal transition (46).…”

Section: Overexpression Of Kibra Rescues the Migration And Adhesionmentioning

confidence: 99%

“…This upstream regulator of Hippo pathway (40)(41)(42) controls the activity of the transcriptional coactivator YAP through its interaction with large-tumor suppressor kinase 1 (LATS1) and LATS2 kinases (42). Alongside these characterized functions in Hippo signaling, recent studies have revealed a role for KIBRA in cell migration and polarization (43)(44)(45). Overexpression of KIBRA can inhibit migration of MCF10A cells (44).…”

Section: Overexpression Of Kibra Rescues the Migration And Adhesionmentioning

confidence: 99%

Human phosphatase CDC14A is recruited to the cell leading edge to regulate cell migration and adhesion

Chen

Uddin

Voit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cell adhesion and migration are highly dynamic biological processes that play important roles in organ development and cancer metastasis. Their tight regulation by small GTPases and protein phosphorylation make interrogation of these key processes of great importance. We now show that the conserved dualspecificity phosphatase human cell-division cycle 14A (hCDC14A) associates with the actin cytoskeleton of human cells. To understand hCDC14A function at this location, we manipulated native loci to ablate hCDC14A phosphatase activity (hCDC14A PD ) in untransformed hTERT-RPE1 and colorectal cancer (HCT116) cell lines and expressed the phosphatase in HeLa FRT T-Rex cells. Ectopic expression of hCDC14A induced stress fiber formation, whereas stress fibers were diminished in hCDC14A PD cells. hCDC14A PD cells displayed faster cell migration and less adhesion than wild-type controls. hCDC14A colocalized with the hCDC14A substrate kidneyand brain-expressed protein (KIBRA) at the cell leading edge and overexpression of KIBRA was able to reverse the phenotypes of hCDC14A PD cells. Finally, we show that ablation of hCDC14A activity increased the aggressive nature of cells in an in vitro tumor formation assay. Consistently, hCDC14A is down-regulated in many tumor tissues and reduced hCDC14A expression is correlated with poorer survival of patients with cancer, to suggest that hCDC14A may directly contribute to the metastatic potential of tumors. Thus, we have uncovered an unanticipated role for hCDC14A in cell migration and adhesion that is clearly distinct from the mitotic and cytokinesis functions of Cdc14/Flp1 in budding and fission yeast.CDC14 | cell migration | cell adhesion | phosphatase

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PTPN14 Forms a Complex with Kibra and LATS1 Proteins and Negatively Regulates the YAP Oncogenic Function

Cited by 79 publications

References 40 publications

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

MiR-21 promotes intrahepatic cholangiocarcinoma proliferation and growth in vitro and in vivo by targeting PTPN14 and PTEN

Human phosphatase CDC14A is recruited to the cell leading edge to regulate cell migration and adhesion

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