A Secreted PTEN Phosphatase That Enters Cells to Alter Signaling and Survival

Hopkins, Benjamin D.; Fine, Barry; Steinbach, Nicole; Dendy, Meaghan; Rapp, Zachary; Shaw, Jacquelyn; Pappas, Kyrie; Yu, Jennifer; Hodakoski, Cindy; Mense, Sarah M.; Klein, J.; Pegno, Sarah; Sulis, Maria Luisa; Goldstein, Hannah; Amendolara, Benjamin; Liu, Liang; Maurer, Matthew; Bruce, Jeffrey N.; Canoll, Peter; Hibshoosh, Hanina; Parsons, Ramon

doi:10.1126/science.1234907

Cited by 278 publications

(391 citation statements)

References 25 publications

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“…Mutation of Pten in the tumour stroma is sufficient to facilitate breast cancer initiation 33,42 , implying an important function for downregulation of Pten in tumour-associated fibroblasts. Indeed, it has been demonstrated recently that Pten can be secreted and taken up by adjacent cells 43 , raising the possibility that elimination of Pten in fibroblasts is necessary to remove a secondary source of secreted Pten that would otherwise be taken up by adjacent tumour cells. K-Ras mutation also drives sarcoma initiation 28 where ZEB1 is induced and Pten is likewise downregulated as opposed to mutated [28][29][30][31][32] .…”

Section: Discussionmentioning

confidence: 99%

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

Liu

Huang

et al. 2014

Nat Commun

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Ras pathway mutation is frequent in carcinomas where it induces expression of the transcriptional repressor ZEB1. Although ZEB1 is classically linked to epithelial-mesenchymal transition and tumour metastasis, it has an emerging second role in generation of cancerinitiating cells. Here we show that Ras induction of ZEB1 is required for tumour initiation in a lung cancer model, and we link this function to repression Pten, whose loss is critical for emergence of cancer-initiating cells. These two roles for ZEB1 in tumour progression can be distinguished by their requirement for different levels of ZEB1. A lower threshold of ZEB1 is sufficient for cancer initiation, whereas further induction is necessary for tumour metastasis.

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Section: Discussionmentioning

confidence: 99%

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

Liu

Huang

et al. 2014

Nat Commun

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“…Moreover, it harbors a secretion signal sequence and a poly-arginine stretch as a signal sequence for entering cells, similar to the poly-basic residues of the human immunodeficiency virus (HIV) trans-activator of transcription (TAT) protein. 8 Functionally, PTEN-L is fivefold more effective at binding to its substrate PtdIns(3,4,5)P3 than PTEN. 24 However, PTEN can be exported in exosomes.…”

Section: Pten and Tumor Suppressionmentioning

confidence: 99%

“…8 PTEN has four functional domains, including an N-terminal phosphatase domain (aa 1-185), a C2 domain (aa 186-349), a C-tail (carboxyl-terminal) domain and a PDZ-BD (PDZ-binding) domain 9 (Figure 1a).…”

Section: Pten and Tumor Suppressionmentioning

confidence: 99%

The functions of tumor suppressor PTEN in innate and adaptive immunity

Chen

Guo

2017

Cell Mol Immunol

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The tumor suppressor phosphatase and tensin homolog (PTEN) is a lipid and protein phosphatase that is able to antagonize the PI3K/AKT pathway and inhibit tumor growth. PTEN also possesses phosphatase-independent functions. Genetic alterations of PTEN may lead to the deregulation of cell proliferation, survival, differentiation, energy metabolism and cellular architecture and mobility. Although the role of PTEN in tumor suppression is extensively documented and well established, the evidence for its roles in immunity did not start to accumulate until recently. In this review, we will focus on the newly discovered functions of PTEN in the regulation of innate and adaptive immunity, including antiviral responses.

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“…PTEN‐long has additional 173 amino acids added to N‐terminal of the canonical PTEN. It has also been verified that PTEN‐long is able to negatively regulate PI3K‐Akt pathway activity much like the canonical PTEN activity 18. PTEN‐long has a low expression level but can be secreted in paracrine manner into plasma and impact neighbouring cells or impact distant cells via the circulatory system 19.…”

Section: Introductionmentioning

confidence: 99%

Expression of PTEN‐long mediated by CRISPR/Cas9 can repress U87 cell proliferation

Fang

Wang

et al. 2017

J Cellular Molecular Medi

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PTEN is a tumour suppressor that is frequently mutated in a variety of cancers. Hence, PTEN has significant potential as a therapeutic molecule. PTEN‐long is an alternative translation variant, with an additional 173 amino acids added to the N‐terminal of the canonical PTEN when CUG of the mRNA is utilized as the start codon. PTEN‐long is secreted into serum and can re‐enter cells throughout the body. One of the major barriers for gene therapy is to efficiently and specifically deliver DNA or RNA material to target cells. As an alternative approach, if a therapeutic protein can be directly delivered to target cell of interest, it should theoretically function well within the cells, particularly for genes that are deficiently expressed in vivo. Most therapeutic proteins are incapable of efficiently permeating the cell membrane. In this study, we have employed CRISPR/Cas9 gene editing tool combined with single‐stranded template to edit CTG of PTEN‐long to ATG in the genome. Two guide RNAs close to CTG site were found to have similar efficiency in driving PTEN‐long expression. Furthermore, we detected PTEN‐long expression in transfected whole‐cell lysate and in concentrated culture media in Western blot. Interestingly, the culture media of PTEN‐long expression can reduce Akt phosphorylation level and repress U87 cell proliferation compared to wild‐type U87 or control media. Taken together, PTEN‐long driven by CRISPR/Cas9 imports and exports cells and represses nearby cell proliferation, indicating the PTEN‐long generated by CRISPR/Cas9 has potential to be an alternative strategy for PTEN gene therapy.

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A Secreted PTEN Phosphatase That Enters Cells to Alter Signaling and Survival

Cited by 278 publications

References 25 publications

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

The functions of tumor suppressor PTEN in innate and adaptive immunity

Expression of PTEN‐long mediated by CRISPR/Cas9 can repress U87 cell proliferation

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