RT Journal Article
SR Electronic
T1 Proteomic Analysis Defines Kinase Taxonomies Specific for Subtypes of Breast Cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 122739
DO 10.1101/122739
A1 K. A.L. Collins
A1 T. J. Stuhlmiller
A1 J. S. Zawistowski
A1 M. P. East
A1 T. Pham
A1 C. R. Hall
A1 D. R. Goulet
A1 S. M. Bevill
A1 S. P. Angus
A1 S. H. Velarde
A1 N. Sciaky
A1 L. M. Graves
A1 G. L. Johnson
A1 S. M. Gomez
YR 2017
UL http://biorxiv.org/content/early/2017/04/01/122739.abstract
AB Multiplexed small molecule inhibitors covalently bound to Sepharose beads (MIBs) were used to capture functional kinases in luminal, HER2-enriched and triple negative, basal-like and claudin-low breast cancer cell lines and tumors. Kinase MIB-binding profiles at baseline without perturbation were significantly uncorrelated to transcript abundance for many kinases and proteomically distinguished the four breast cancer subtypes. Understudied kinases were highly represented in the MIB-binding taxonomies and shown to be integrated in kinase signaling subnetworks with characterized kinases. Computationally it was possible to define subtypes using profiles of only 50 of the more than 300 kinases bound to MIBs that included understudied as well as metabolic and lipid kinases (22 of 50 were understudied). MIB-binding profiles readily defined subtype-selective differential adaptive kinome reprogramming in response to targeted kinase inhibition. Comprehensive MIBs-based capture of kinases provides a unique proteomics-based method for defining functional kinome dynamics and subnetworks in cells and tumors that integrates poorly characterized kinases of the understudied kinome that is not possible using genomic strategies.