Maximal entropy inference of oncogenicity from phosphorylation signaling.
Point mutations in the phosphorylation domain of the Bcr-Abl fusion oncogene give rise to drug resistance in chronic myelogenous leukemia patients. These mutations alter kinase-mediated signaling function and phenotypic outcome. An information theoretic analysis of the correlation of phosphoproteomic profiling and transformation potency of the oncogene in different mutants is presented. The theory seeks to predict the leukemic transformation potency from the observed signaling by constructing a distribution of maximal entropy of site-specific phosphorylation events. The theory is developed with special reference to systems biology where high throughput measurements are typical. We seek sets of phosphorylation events most contributory to predicting the phenotype by determining the constraints on the signaling system. The relevance of a constraint is measured by how much it reduces the value of the entropy from its global maximum, where all events are equally likely. Application to experimental phospho-proteomics data for kinase inhibitor-resistant mutants shows that there is one dominant constraint and that other constraints are not relevant to a similar extent. This single constraint accounts for much of the correlation of phosphorylation events with the oncogenic potency and thereby usefully predicts the trends in the phenotypic output. An additional constraint possibly accounts for biological fine structure.
Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, University of California, Los Angeles, CA 90095, USA.
T G
TG
Graeber
J R
JR
Heath
B J
BJ
Skaggs
M E
ME
Phelps
F
F
Remacle
R D
RD
Levine
D000595:Amino Acid Sequence; D019277:Entropy; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics; D016313:Genes, abl; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009857:Oncogenes; D010641:Phenotype; D010766:Phosphorylation; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics; D040901:Proteomics; D015398:Signal Transduction; D049490:Systems Biology
D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl