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PIPKI? regulates ?-catenin transcriptional activity downstream of growth factor receptor signaling.

ABSTRACT: Increased ?-catenin transcriptional activity downstream of the Wnt/Wingless signaling pathway has been observed in many human tumors, most notably colorectal carcinomas. However, ?-catenin activation is also observed in many human malignancies with no observable Wnt activity. Wnt-independent pathways that activate ?-catenin remain undefined, yet have the potential to play a significant role during tumorigenesis. Here, we report that phosphotidylinositol phosphate kinase I? (PIPKI?), an enzyme that generates phosphoinositide messengers in vivo, directly associates with ?-catenin and increases ?-catenin activity downstream of growth factor stimulation. PIPKI? expression and kinase activity enhance ?-catenin phosphorylation on residues that promote nuclear importation and transcriptional activity. Lastly, we show that ?-catenin is required for PIPKI?-dependent increased cell proliferation. These results reveal a novel mechanism in which PIPKI? expression and catalytic activity enhance ?-catenin nuclear translocation and expression of its target genes to promote tumorigenic phenotypes.

SUBMITTER: Schramp M

PROVIDER: S-EPMC3066690 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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PIPKIγ regulates β-catenin transcriptional activity downstream of growth factor receptor signaling.

Schramp Mark M Thapa Narendra N Heck Jessica J Anderson Richard R

Cancer research 20110208 4

Increased β-catenin transcriptional activity downstream of the Wnt/Wingless signaling pathway has been observed in many human tumors, most notably colorectal carcinomas. However, β-catenin activation is also observed in many human malignancies with no observable Wnt activity. Wnt-independent pathways that activate β-catenin remain undefined, yet have the potential to play a significant role during tumorigenesis. Here, we report that phosphotidylinositol phosphate kinase Iγ (PIPKIγ), an enzyme th ...[more]

PMID: 21303971

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Project description:BACKGROUND:Spleen tyrosine kinase (SYK) is frequently upregulated in recurrent ovarian carcinomas, for which effective therapy is urgently needed. SYK phosphorylates several substrates, but their translational implications remain unclear. Here, we show that SYK interacts with EGFR and ERBB2, and directly enhances their phosphorylation. METHODS:We used immunohistochemistry and immunoblotting to assess SYK and EGFR phosphorylation in ovarian serous carcinomas. Association with survival was determined by Kaplan-Meier analysis and the log-rank test. To study its role in EGFR signaling, SYK activity was modulated using a small molecule inhibitor, a syngeneic knockout, and an active kinase inducible system. We applied RNA-seq and phosphoproteomic mass spectrometry to investigate the SYK-regulated EGF-induced transcriptome and downstream substrates. FINDINGS:Induced expression of constitutively active SYK130E reduced cellular response to EGFR/ERBB2 inhibitor, lapatinib. Expression of EGFRWT, but not SYK non-phosphorylatable EGFR3F mutant, resulted in paclitaxel resistance, a phenotype characteristic to SYK active ovarian cancers. In tumor xenografts, SYK inhibitor reduces phosphorylation of EGFR substrates. Compared to SYKWT cells, SYKKO cells have an attenuated EGFR/ERBB2-transcriptional activity and responsiveness to EGF-induced transcription. In ovarian cancer tissues, pSYK (Y525/526) levels showed a positive correlation with pEGFR (Y1187). Intense immunoreactivity of pSYK (Y525/526) correlated with poor overall survival in ovarian cancer patients. INTERPRETATION:These findings indicate that SYK activity positively modulates the EGFR pathway, providing a biological foundation for co-targeting SYK and EGFR. FUND: Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, NIH/NCI, Ovarian Cancer Research Foundation Alliance, HERA Women's Cancer Foundation and Roseman Foundation. Funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript and eventually in the decision to submit the manuscript.

Dataset Information

PIPKI? regulates ?-catenin transcriptional activity downstream of growth factor receptor signaling.

Publications

PIPKIγ regulates β-catenin transcriptional activity downstream of growth factor receptor signaling.

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