PRR14 is a Novel Activator of the PI3K Pathway Promoting Lung Carcinogenesis

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2016 Apr 5

PMID 27041574

Citations 13

Authors

M Yang

M Lewinska

X Fan

J Zhu

Z-M Yuan

Affiliations

Soon will be listed here.

Abstract

Chromosomal focal amplifications often cause an increase in gene copy number, contributing to the pathogenesis of cancer. PRR14 overexpression is associated with recurrent locus amplification in lung cancer, and it correlates with a poor prognosis. We show that increased PRR14 expression promoted and reduced PRR14 expression impeded lung cancer cell proliferation. Interestingly, PRR14 cells were markedly enlarged in size and exhibited an elevated activity of the PI3-kinase/Akt/mTOR pathway, which was associated with a heightened sensitivity to the inhibitors of PI3K and mammalian target of rapamycin (mTOR). Biochemical analysis revealed that PRR14, as a proline-rich protein, binds to the Src homology 3 (SH3) domains of GRB2 resulting in PI3K activation. Significantly, two cancer patient-derived PRR14 mutants displayed considerably augmented GRB2-binding and an enhanced ability of promoting cell proliferation. Together with the in vivo data demonstrating a strong tumor-promoting activity of PRR14 and the mutants, our work uncovered this proline-rich protein as a novel activator of the PI3K pathway that promoted tumorigenesis in lung cancer.

Citing Articles

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References

Yang Y, Garbay C, Duchesne M, Cornille F, Jullian N, Fromage N . Solution structure of GAP SH3 domain by 1H NMR and spatial arrangement of essential Ras signaling-involved sequence. EMBO J. 1994; 13(6):1270-9. PMC: 394941. DOI: 10.1002/j.1460-2075.1994.tb06379.x. View

Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P . Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature. 1993; 363(6424):85-8. DOI: 10.1038/363085a0. View

Cheng H, Shcherba M, Pendurti G, Liang Y, Piperdi B, Perez-Soler R . Targeting the PI3K/AKT/mTOR pathway: potential for lung cancer treatment. Lung Cancer Manag. 2014; 3(1):67-75. PMC: 4203662. DOI: 10.2217/lmt.13.72. View

Brognard J, Clark A, Ni Y, Dennis P . Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res. 2001; 61(10):3986-97. View

Yang X, Xu T . Molecular mechanism of size control in development and human diseases. Cell Res. 2011; 21(5):715-29. PMC: 3203678. DOI: 10.1038/cr.2011.63. View

Lysek D, Wuthrich K . Prion protein interaction with the C-terminal SH3 domain of Grb2 studied using NMR and optical spectroscopy. Biochemistry. 2004; 43(32):10393-9. DOI: 10.1021/bi0494828. View

Castellano E, Downward J . Role of RAS in the regulation of PI 3-kinase. Curr Top Microbiol Immunol. 2010; 346:143-69. DOI: 10.1007/82_2010_56. View

Lin X, Bohle A, Dohrmann P, Leuschner I, Schulz A, Kremer B . Overexpression of phosphatidylinositol 3-kinase in human lung cancer. Langenbecks Arch Surg. 2001; 386(4):293-301. DOI: 10.1007/s004230100203. View

Chardin P, Camonis J, Gale N, Van Aelst L, Schlessinger J, Wigler M . Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science. 1993; 260(5112):1338-43. DOI: 10.1126/science.8493579. View

10.

Poleshko A, Mansfield K, Burlingame C, Andrake M, Shah N, Katz R . The human protein PRR14 tethers heterochromatin to the nuclear lamina during interphase and mitotic exit. Cell Rep. 2013; 5(2):292-301. PMC: 3867587. DOI: 10.1016/j.celrep.2013.09.024. View

11.

Guruprasad L, Dhanaraj V, Timm D, Blundell T, Gout I, Waterfield M . The crystal structure of the N-terminal SH3 domain of Grb2. J Mol Biol. 1995; 248(4):856-66. DOI: 10.1006/jmbi.1995.0266. View

12.

Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne P, Downward J . Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 1997; 16(10):2783-93. PMC: 1169887. DOI: 10.1093/emboj/16.10.2783. View

13.

Kennedy S, Wagner A, Conzen S, Jordan J, Bellacosa A, Tsichlis P . The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 1997; 11(6):701-13. DOI: 10.1101/gad.11.6.701. View

14.

Booker G, Gout I, Downing A, Driscoll P, Boyd J, Waterfield M . Solution structure and ligand-binding site of the SH3 domain of the p85 alpha subunit of phosphatidylinositol 3-kinase. Cell. 1993; 73(4):813-22. DOI: 10.1016/0092-8674(93)90259-s. View

15.

Wissmueller S, Font J, Liew C, Cram E, Schroeder T, Turner J . Protein-protein interactions: analysis of a false positive GST pulldown result. Proteins. 2011; 79(8):2365-71. DOI: 10.1002/prot.23068. View

16.

Spoerke J, OBrien C, Huw L, Koeppen H, Fridlyand J, Brachmann R . Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin Cancer Res. 2012; 18(24):6771-83. DOI: 10.1158/1078-0432.CCR-12-2347. View

17.

Jimenez C, Jones D, Rodriguez-Viciana P, Gonzalez-Garcia A, Leonardo E, Wennstrom S . Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. EMBO J. 1998; 17(3):743-53. PMC: 1170423. DOI: 10.1093/emboj/17.3.743. View

18.

Kamburov A, Stelzl U, Lehrach H, Herwig R . The ConsensusPathDB interaction database: 2013 update. Nucleic Acids Res. 2012; 41(Database issue):D793-800. PMC: 3531102. DOI: 10.1093/nar/gks1055. View

19.

Klippel A, Escobedo M, Wachowicz M, Apell G, Brown T, Giedlin M . Activation of phosphatidylinositol 3-kinase is sufficient for cell cycle entry and promotes cellular changes characteristic of oncogenic transformation. Mol Cell Biol. 1998; 18(10):5699-711. PMC: 109156. DOI: 10.1128/MCB.18.10.5699. View

20.

Fingar D, Salama S, Tsou C, Harlow E, Blenis J . Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 2002; 16(12):1472-87. PMC: 186342. DOI: 10.1101/gad.995802. View