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CK2β is a gatekeeper of focal adhesions regulating cell spreading

ABSTRACT: CK2 is an hetero-tetrameric protein made of two CK2α catalytic subunits and two regulatory CK2β subunits. The free CK2α subunit and the tetrameric holoenzyme have distinct substrate specificity profiles suggesting that the spatiotemporal organization of the individual CK2 subunits observed in living cells is crucial in the control of the many cellular processes that are governed by this pleiotropic kinase. Indeed, sub-stoichiometric expression of CK2β compared to CK2α in a subset of breast cancer tumors was correlated with the induction of EMT markers and increased epithelial cell plasticity in breast carcinoma progression. Using phosphotyrosine profiling with affinity capture and LC/MS-MS, we show that decreased expression of CK2β in MCF10A mammary epithelial cells triggers the phosphorylation of a number of tyrosine phosphorylated proteins and promotes the striking activation of the FAK1-Src-PAX1 signaling pathway. Moreover, morphometric analyses also revealed that CK2β loss increases the number and the spatial distribution of focal adhesion signaling complexes. Together, our finding allows positioning CK2β as a gatekeeper for cell spreading by restraining the focal adhesion maturation and invasion of mammary epithelial cells.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Mammary Gland Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: Hesse Anne-Marie

LAB HEAD: Yohann Couté

PROVIDER: PXD030991 | Pride | 2022-07-05

REPOSITORIES: Pride

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Project description:Background Annexin-1 (ANXA1) plays pivotal roles in regulating various physiological processes including inflammation, proliferation and apoptosis, and deregulations of ANXA1 functions have been associated with tumorigenesis and metastasis events in several cancers. 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 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 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 8,110 unique phosphorylation sites, of which 582 phosphorylation sites on 372 proteins showed 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 pressing on 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 stressed on a close-coordinated rewiring of the cell adhesion network. Kinase prediction analysis suggested activity modulation of CAMK2, PAK, ERK, and IKK kinases upon loss of ANXA1. Integrative analysis revealed regulation of WNT and also Hippo signaling pathways in ANXA1-deficient mammary epithelial cells, wherein there is a downregulation of transcriptional effects of TEAD suggestive of ANXA1-responsive transcriptional rewiring. Conclusions The phosphoproteome landscape uncovered several novel perspectives for ANXA1 in mammary gland biology and stressed on its involvement in key signaling pathways modulating cell adhesion and migration that could contribute to breast cancer initiation.

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CK2β is a gatekeeper of focal adhesions regulating cell spreading

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