Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression.
Dominant mutations or DNA amplification of tyrosine kinases are rare among the oncogenic alterations implicated in prostate cancer. We demonstrate that castration-resistant prostate cancer (CRPC) in men exhibits increased tyrosine phosphorylation, raising the question of whether enhanced tyrosine kinase activity is observed in prostate cancer in the absence of specific tyrosine kinase mutation or DNA amplification. We generated a mouse model of prostate cancer progression using commonly perturbed non-tyrosine kinase oncogenes and pathways and detected a significant up-regulation of tyrosine phosphorylation at the carcinoma stage. Phosphotyrosine peptide enrichment and quantitative mass spectrometry identified oncogene-specific tyrosine kinase signatures, including activation of EGFR, ephrin type-A receptor 2 (EPHA2), and JAK2. Kinase:substrate relationship analysis of the phosphopeptides also revealed ABL1 and SRC tyrosine kinase activation. The observation of elevated tyrosine kinase signaling in advanced prostate cancer and identification of specific tyrosine kinase pathways from genetically defined tumor models point to unique therapeutic approaches using tyrosine kinase inhibitors for advanced prostate cancer.
Department of Microbiology, Immunology, and Molecular Genetics, Crump Institute for Molecular Imaging, Institute for Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Justin M
JM
Drake
Nicholas A
NA
Graham
Tanya
T
Stoyanova
Amir
A
Sedghi
Andrew S
AS
Goldstein
Houjian
H
Cai
Daniel A
DA
Smith
Hong
H
Zhang
Evangelia
E
Komisopoulou
Jiaoti
J
Huang
Thomas G
TG
Graeber
Owen N
ON
Witte
D000818:Animals; D004789:Enzyme Activation; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D009857:Oncogenes; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D040901:Proteomics; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D014443:Tyrosine; D011505:Protein-Tyrosine Kinases