title: Α-tubulin K40 acetylation is required for contact inhibition of proliferation and cell-substrate adhesion.
abstract: Acetylation of α-tubulin on lysine 40 marks long-lived microtubules in structures such as axons and cilia, and yet the physiological role of α-tubulin K40 acetylation is elusive. Although genetic ablation of the α-tubulin K40 acetyltransferase αTat1 in mice did not lead to detectable phenotypes in the developing animals, contact inhibition of proliferation and cell-substrate adhesion were significantly compromised in cultured αTat1(-/-) fibroblasts. First, αTat1(-/-) fibroblasts kept proliferating beyond the confluent monolayer stage. Congruently, αTat1(-/-) cells failed to activate Hippo signaling in response to increased cell density, and the microtubule association of the Hippo regulator Merlin was disrupted. Second, αTat1(-/-) cells contained very few focal adhesions, and their ability to adhere to growth surfaces was greatly impaired. Whereas the catalytic activity of αTAT1 was dispensable for monolayer formation, it was necessary for cell adhesion and restrained cell proliferation and activation of the Hippo pathway at elevated cell density. Because α-tubulin K40 acetylation is largely eliminated by deletion of αTAT1, we propose that acetylated microtubules regulate contact inhibition of proliferation through the Hippo pathway.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Andrea
authors.initials: A
authors.lastname: Aguilar
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Lars
authors.initials: L
authors.lastname: Becker
authors.affiliation: Departments of Ophthalmology and of Developmental and Regenerative Biology, Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tedeschi
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Stefan
authors.initials: S
authors.lastname: Heller
authors.affiliation: Departments of Ophthalmology and of Developmental and Regenerative Biology, Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029.
authors.forename: Carlo
authors.initials: C
authors.lastname: Iomini
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305 nachury@stanford.edu.
authors.forename: Maxence V
authors.initials: MV
authors.lastname: Nachury
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D000090683:Hippo Signaling Pathway; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008868:Microtubule Proteins; D008870:Microtubules / Q000378:metabolism; D025581:Neurofibromin 2 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D014404:Tubulin / Q000378:metabolism*
chemical_list: D008868:Microtubule Proteins; D025581:Neurofibromin 2; D014404:Tubulin; D000123:Acetyltransferases; C583619:ATAT1 protein, mouse; D017346:Protein Serine-Threonine Kinases
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