Please use this identifier to cite or link to this item: https://doi.org/10.1186/s13058-017-0924-4
Title: Phosphoproteomics reveals network rewiring to a pro-adhesion state in annexin-1-deficient mammary epithelial cells
Authors: Alli-Shaik, A
Wee, S
Lim, L.H.K 
Gunaratne, J 
Keywords: calcium calmodulin dependent protein kinase II
I kappa B kinase beta
lipocortin 1
mitogen activated protein kinase
p21 activated kinase
annexin A1, mouse
lipocortin 1
phosphoprotein
proteome
animal cell
Article
breast epithelium cell
cell adhesion
controlled study
down regulation
focal adhesion
hippo signaling
isotope labeling
mass spectrometry
microtubule assembly
mouse
nonhuman
phosphoproteomics
protein phosphorylation
protein processing
signal transduction
stress fiber
Wnt signaling
animal
biology
cell adhesion
cluster analysis
deficiency
epithelium cell
female
gene knockout
genetics
human
metabolism
procedures
protein analysis
proteomics
udder
Animals
Annexin A1
Cell Adhesion
Cluster Analysis
Computational Biology
Epithelial Cells
Female
Gene Knockout Techniques
Humans
Mammary Glands, Animal
Mice
Phosphoproteins
Protein Interaction Mapping
Protein Interaction Maps
Proteome
Proteomics
Issue Date: 2017
Publisher: BioMed Central Ltd.
Citation: Alli-Shaik, A, Wee, S, Lim, L.H.K, Gunaratne, J (2017). Phosphoproteomics reveals network rewiring to a pro-adhesion state in annexin-1-deficient mammary epithelial cells. Breast Cancer Research 19 (1) : 132. ScholarBank@NUS Repository. https://doi.org/10.1186/s13058-017-0924-4
Rights: Attribution 4.0 International
Abstract: Background: Annexin-1 (ANXA1) plays pivotal roles in regulating various physiological processes including inflammation, proliferation and apoptosis, and deregulation of ANXA1 functions has been associated with tumorigenesis and metastasis events in several types of cancer. Though ANXA1 levels correlate with breast cancer disease status and outcome, its distinct functional involvement in breast cancer initiation and progression remains unclear. We hypothesized that ANXA1-responsive kinase signaling alteration and associated phosphorylation signaling underlie early events in breast cancer initiation events and hence profiled ANXA1-dependent phosphorylation changes in mammary gland epithelial cells. Methods: Quantitative phosphoproteomics analysis of mammary gland epithelial cells derived from ANXA1-heterozygous and ANXA1-deficient mice was carried out using stable isotope labeling with amino acids in cell culture (SILAC)-based mass spectrometry. Kinase and signaling changes underlying ANXA1 perturbations were derived by upstream kinase prediction and integrated network analysis of altered proteins and phosphoproteins. Results: We identified a total of 8110 unique phosphorylation sites, of which 582 phosphorylation sites on 372 proteins had ANXA1-responsive changes. A majority of these phosphorylation changes occurred on proteins associated with cytoskeletal reorganization spanning the focal adhesion, stress fibers, and also the microtubule network proposing new roles for ANXA1 in regulating microtubule dynamics. Comparative analysis of regulated global proteome and phosphoproteome highlighted key differences in translational and post-translational effects of ANXA1, and suggested closely coordinated rewiring of the cell adhesion network. Kinase prediction analysis suggested activity modulation of calmodulin-dependent protein kinase II (CAMK2), P21-activated kinase (PAK), extracellular signal-regulated kinase (ERK), and I?B kinase (IKK) upon loss of ANXA1. Integrative analysis revealed regulation of the WNT and Hippo signaling pathways in ANXA1-deficient mammary epithelial cells, wherein there is downregulation of transcriptional effects of TEA domain family (TEAD) suggestive of ANXA1-responsive transcriptional rewiring. Conclusions: The phosphoproteome landscape uncovered several novel perspectives for ANXA1 in mammary gland biology and highlighted its involvement in key signaling pathways modulating cell adhesion and migration that could contribute to breast cancer initiation. © 2017 The Author(s).
Source Title: Breast Cancer Research
URI: https://scholarbank.nus.edu.sg/handle/10635/183471
ISSN: 1465-5411
DOI: 10.1186/s13058-017-0924-4
Rights: Attribution 4.0 International
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