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Mol Cell Biol. 2015 May;35(9):1506-22. doi: 10.1128/MCB.01206-14. Epub 2015 Mar 2.

Brk/Protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin D-cyclin-dependent kinase 4.

Author information

1
School of Graduate Studies, SUNY Downstate Medical Center, Brooklyn, New York, USA.
2
Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
3
Departments of Pediatrics and Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, USA.
4
College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, USA.
5
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, USA.
6
Departments of Pediatrics and Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, USA stacy.blain@downstate.edu.

Abstract

Cyclin D and cyclin-dependent kinase 4 (cdk4) are overexpressed in a variety of tumors, but their levels are not accurate indicators of oncogenic activity because an accessory factor such as p27(Kip1) is required to assemble this unstable dimer. Additionally, tyrosine (Y) phosphorylation of p27 (pY88) is required to activate cdk4, acting as an "on/off switch." We identified two SH3 recruitment domains within p27 that modulate pY88, thereby modulating cdk4 activity. Via an SH3-PXXP interaction screen, we identified Brk (breast tumor-related kinase) as a high-affinity p27 kinase. Modulation of Brk in breast cancer cells modulates pY88 and increases resistance to the cdk4 inhibitor PD 0332991. An alternatively spliced form of Brk (Alt Brk) which contains its SH3 domain blocks pY88 and acts as an endogenous cdk4 inhibitor, identifying a potentially targetable regulatory region within p27. Brk is overexpressed in 60% of breast carcinomas, suggesting that this facilitates cell cycle progression by modulating cdk4 through p27 Y phosphorylation. p27 has been considered a tumor suppressor, but our data strengthen the idea that it should also be considered an oncoprotein, responsible for cyclin D-cdk4 activity.

PMID:
25733683
PMCID:
PMC4387217
DOI:
10.1128/MCB.01206-14
[Indexed for MEDLINE]
Free PMC Article

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