title: MEKK1 regulates calpain-dependent proteolysis of focal adhesion proteins for rear-end detachment of migrating fibroblasts.
abstract: Herein, we define how MEKK1, a MAPK kinase kinase, regulates cell migration. MEKK1 is associated with actin fibers and focal adhesions, localizing MEKK1 to sites critical in the control of cell adhesion and migration. EGF-induced ERK1/2 activation and chemotaxis are inhibited in MEKK1-/- fibroblasts. MEKK1 deficiency causes loss of vinculin in focal adhesions of migrating cells, increased cell adhesion and impeded rear-end detachment. MEKK1 is required for activation of the cysteine protease calpain and cleavage of spectrin and talin, proteins linking focal adhesions to the cytoskeleton. Inhibition of ERK1/2 or calpain, but not of JNK, mimics MEKK1 deficiency. Therefore, MEKK1 regulates calpain-mediated substratum release of migrating fibroblasts.
authors.affiliation: Department of Pharmacology, Craniofacial Biology, University of Colorado Health Sciences Center, Denver, CO 80262, USA. bruce.cuevas@uchsc.edu
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Cuevas
authors.forename: Amy N
authors.initials: AN
authors.lastname: Abell
authors.forename: James A
authors.initials: JA
authors.lastname: Witowsky
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yujiri
authors.forename: Nancy Lassignal
authors.initials: NL
authors.lastname: Johnson
authors.forename: Kamala
authors.initials: K
authors.lastname: Kesavan
authors.forename: Marti
authors.initials: M
authors.lastname: Ware
authors.forename: Peter L
authors.initials: PL
authors.lastname: Jones
authors.forename: Scott A
authors.initials: SA
authors.lastname: Weed
authors.forename: Roberta L
authors.initials: RL
authors.lastname: DeBiasi
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Tyler
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
mesh_terms: D000818:Animals; D002154:Calpain / Q000502:physiology*; D002465:Cell Movement; D002478:Cells, Cultured; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005453:Fluorescence; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006868:Hydrolysis; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D027383:Papillomaviridae / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism*
chemical_list: D016596:Vinculin; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse; D002154:Calpain