Biophysical Society Thematic Meeting| Aussois 2019

Biology and Physics Confront Cell-Cell Adhesion

Tuesday Speaker Abstracts

SHAPING CELL CONTACTS DURING TISSUE MORPHOGENESIS Pierre-François Lenne Aix Marseille University, CNRS, IBDM, Marseille, France

During animal morphogenesis cell contacts are constantly remodeled. This stems from active contractile forces that work against adhesive forces at cell contacts. Using physical approaches including super-resolution imaging, optical manipulation and modeling, we study the mechanics and the supramolecular organization of cell contacts during morphogenesis. In the first part of my talk, I will show how active contractile forces interact with adhesive forces to remodel cell contacts in the Drosophila embryo. In the second part, I will describe the supramolecular organization of the zonula adherens with super-resolution imaging and show that nectin rather than E-cadherin anchors the actin belt within simple columnar epithelia.

MECHANICAL REGULATION OF PARACRINE GROWTH FACTOR SIGNALING Willem-Jan Pannekoek 1 ; Ronja M Houtekamer 1 ; Marjolein J Vliem 1 ; Lisa van Uden 1 ; Robert M van Es 1 ; Harmjan R Vos 1 ; Martijn Gloerich 1 ; 1 University Medical Center Utrecht, Molecular Cancer Research, Center for Molecular Medicine, Utrecht, The Netherlands Epithelial cells exert tensile forces on each other that are transduced by adherens junctions (AJs) to control cell proliferation, differentiation, migration and metabolism. Despite our growing knowledge on force-sensitive cellular processes, the underlying signal transduction pathways that are regulated by fluctuations in tension on AJs remain largely elusive. Here, we uncover tension-sensitive signal transduction pathways using proteome-wide analysis of phosphorylation changes in epithelial monolayers subjected to mechanical stretch. This reveals stretch-induced activation of the MAP kinases ERK1 and ERK2, which we show to require force transduction by AJs. Mechanical stretch induces the entire EGFR/Ras/MEK/ERK pathway, in a manner dependent on ligand binding to EGFR. To elucidate how force transduction by AJs enhances EGFR activity, we performed APEX2-mediated proximity labeling of the core AJ component E- cadherin. This identifies the spatial vicinity of AJs and the metalloproteinase ADAM17, which cleaves the ectodomain of transmembrane EGFR ligands to enable paracrine activation of EGFR. We identify an inhibitory phosphorylation site on ADAM17 that is downregulated upon mechanical stretch, and demonstrate that chemical inhibition of ADAM17 attenuates stretch- induced EGFR and ERK activation. These data uncover a novel mechanism of force-dependent control of cell signaling, comprising AJ-mediated paracrine activation of the EGFR/ERK pathway via ADAM17.

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