Tyrosine phosphorylation of PP2A is regulated by HER-2 signalling and correlates with breast cancer progression.
Activation of HER-2/neu leads to multiple signalling cascades and plays a vital role in cell survival and growth. We used a signal transduction antibody array to characterize the tyrosine phosphorylation profiles in heregulin (HRG alpha1)-treated BT474 breast cancer cells, and identified a group of 80 molecules in which tyrosine phosphorylation was highly regulated by HRG-enhanced HER-2/neu signalling. These phosphoproteins included many known HER-2/neu-regulated molecules (e.g., SHC, Akt, Syk and Stat1) and proteins that had not been previously linked to HER-2/neu signalling, such as Fas-associated death domain protein (FADD), apoptosis repressor with CARD domain (ARC), and the tumour suppressor, protein phosphatase type 2A (PP2A). Pharmacological inhibition with HER-2 inhibitor AG825, PI3K inhibitor LY294002, MEK1/2 inhibitor PD98095, and p38MAPK inhibitor SB203580 confirmed that PP2A phosphorylation was modulated by the complicated, HER-2/neu-driven downstream signal network, with the PI3K and MEK1/2 positively, while the p38MAPK negatively regulating its tyrosine phosphorylation. In breast tumour specimens, expression of tyrosine-phosphorylated PP2A (pY307-PP2A) was highly increased in the HER-2/neu positive breast tumours, and significantly correlated to tumour progression, thus enhancing its potential prognostic value. Our data provide meaningful information in the elucidation of the HER-2-driven tyrosine phosphorylation network, and in the development of phosphopeptide-related targets as prognostication indicators.
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074.
Lee Lee
LL
Wong
Chan Fong
CF
Chang
Evelyn S C
ES
Koay
Daohai
D
Zhang
D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D020890:Neuregulin-1 / Q000494:pharmacology; D010766:Phosphorylation; D011379:Prognosis; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D014408:Biomarkers, Tumor; D020890:Neuregulin-1; D054648:Protein Phosphatase 2; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine; C117463:heregulin alpha