title: Vinculin phosphorylation differentially regulates mechanotransduction at cell-cell and cell-matrix adhesions.
abstract: Cells experience mechanical forces throughout their lifetimes. Vinculin is critical for transmitting these forces, yet how it achieves its distinct functions at cell-cell and cell-matrix adhesions remains unanswered. Here, we show vinculin is phosphorylated at Y822 in cell-cell, but not cell-matrix, adhesions. Phosphorylation at Y822 was elevated when forces were applied to E-cadherin and was required for vinculin to integrate into the cadherin complex. The mutation Y822F ablated these activities and prevented cells from stiffening in response to forces on E-cadherin. In contrast, Y822 phosphorylation was not required for vinculin functions in cell-matrix adhesions, including integrin-induced cell stiffening. Finally, forces applied to E-cadherin activated Abelson (Abl) tyrosine kinase to phosphorylate vinculin; Abl inhibition mimicked the loss of vinculin phosphorylation. These data reveal an unexpected regulatory mechanism in which vinculin Y822 phosphorylation determines whether cadherins transmit force and provides a paradigm for how a shared component of adhesions can produce biologically distinct functions.
authors.affiliation: Department of Biochemistry, University of Iowa Roy J. Carver College of Medicine, Iowa City, IA 52242.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Bays
authors.forename: Xiao
authors.initials: X
authors.lastname: Peng
authors.forename: Catlin E
authors.initials: CE
authors.lastname: Tolbert
authors.forename: Christophe
authors.initials: C
authors.lastname: Guilluy
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Angell
authors.forename: Yuan
authors.initials: Y
authors.lastname: Pan
authors.forename: Richard
authors.initials: R
authors.lastname: Superfine
authors.forename: Keith
authors.initials: K
authors.lastname: Burridge
authors.forename: Kris A
authors.initials: KA
authors.lastname: DeMali
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism; D016596:Vinculin / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; C488955:VCL protein, human; D016596:Vinculin; D016315:Proto-Oncogene Proteins c-abl
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