Myc drives Pten/trp53-deficient proliferation and metastasis due to Il6-secretion and Akt-suppression via Phlpp2

Trotman, L. C., Nowak, D. G., Cho, H., Herzka, T., Watrud, K., DeMarco, D. V., Wang, V. M., Senturk, S., Fellmann, C., Ding, D., Beinortas, T., Kleinman, D., Chen, M., Sordella, R., Wilkinson, J. E., Castillo-Martin, M., Cordon-Cardo, C., Robinson, B. D. (June 2015) Myc drives Pten/trp53-deficient proliferation and metastasis due to Il6-secretion and Akt-suppression via Phlpp2. Cancer Discovery, 5 (6). pp. 636-651. ISSN 21598274

URL: http://www.ncbi.nlm.nih.gov/pubmed/25829425

DOI: 10.1158/2159-8290.cd-14-1113

Abstract

We have recently recapitulated metastasis of human PTEN/ TP53-mutant PC in mouse using the RapidCaP system. Surprisingly, we found that this metastasis is driven by Myc-, and not Akt-activation. Here, we show that cell-cell communication by Il6 drives the Akt-Myc switch through activation of the Akt-suppressing phosphatase Phlpp2, when Pten and p53 are lost together, but not separately. Il6 then communicates a downstream program of Stat3-mediated Myc-activation, which drives cell proliferation. Similarly in tissues, peak proliferation in Pten/ Trp53 mutant primary and metastatic PC does not correlate with activated Akt, but with Stat3/ Myc activation instead. Mechanistically, Myc strongly activates the Akt phosphatase Phlpp2 in primary cells and PC metastasis. We show genetically that Phlpp2 is essential for dictating proliferation of Myc-mediated Akt-suppression. Collectively, our data reveal competition between two proto-oncogenes: Myc and Akt, which ensnarls the Phlpp2 gene to facilitate Myc-driven PC metastasis after loss of Pten and Trp53.

Item Type:	Paper
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Akt diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN diseases & disorders > cancer > metastasis bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
CSHL Authors:	Chen, Muhan Cho, Hyejin Herzka, Tali Nowak, Dawid G. Senturk, Serif Sordella, Raffaella Trotman, Lloyd C. Watrud, Kaitlin
Communities:	CSHL Cancer Center Program > Signal Transduction CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service CSHL Cancer Center Shared Resources > Bioinformatics Service CSHL Cancer Center Shared Resources > Flow Cytometry Service CSHL Cancer Center Shared Resources > Microscopy Service CSHL labs > Sordella lab CSHL labs > Trotman lab CSHL Cancer Center Shared Resources > DNA Sequencing Service
Depositing User:	Matt Covey
Date:	June 2015
Date Deposited:	16 Apr 2015 20:21
Last Modified:	04 Nov 2015 21:25
PMCID:	PMC4456272
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/31315

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