Brk/Protein Tyrosine Kinase 6 Phosphorylates p27KIP1, Regulating the Activity of Cyclin D–Cyclin-Dependent Kinase 4
Authors: Benedikt Asbach
Angela L Tyner
Priyank Patel
Alexander Coltoff
Ralf Wagner
Elina Shteyn
Sadia Bhuyan
Stacy W Blain
Cindy Gomez
Journal: Molecular and Cellular Biology (2015)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Cyclin D; cyclin-dependent kinase 4; p27(Kip1); tyrosine phosphorylation; pY88
Affiliations: School of Graduate Studies, SUNY Downstate Medical Center, Brooklyn, New York, USA., Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany., Departments of Pediatrics and Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, USA., College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, USA., Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, USA., Departments of Pediatrics and Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, USA .

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. 

Retracted: No

PubPeer comments:
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 22 Aug 2022 Expression of Concern. https: journals.asm.org doi 10.1128 mcb.00322-22 The American Society for Microbiology (ASM) and Molecular and Cellular Biology (MCB) are issuing this Expression of Concern regarding the following publication: Patel P, Asbach B, Shteyn E, Gomez C, Coltoff A, Bhuyan S, Tyner AL, Wagner R, Blain SW. 2015. Brk protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin Du2013cyclin-dependent kinase 4. Mol Cell Biol 35(9):1506u20131522. https: doi.org 10.1128 MCB.01206-14. Molecular and Cellular Biology was notified that the above-mentioned paper was investigated by the SUNY Downstate Health Sciences University and that potential image duplications were found in Fig. 2C, H, and I. This Expression of Concern is issued pending the outcome of ongoing litigation between SUNY Downstate Health Sciences University and the corresponding author of the paper, Stacy Blain, in the United States District Court of the Eastern District of New York. , 
 #9 https: ia802504.us.archive.org 22 items gov.uscourts.nyed.480260 gov.uscourts.nyed.480260.1.0.pdf , 
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