MEKK1 regulates calpain-dependent proteolysis of focal adhesion proteins for rear-end detachment of migrating fibroblasts.
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.
Cuevas
Bruce D
BD
Department of Pharmacology, Craniofacial Biology, University of Colorado Health Sciences Center, Denver, CO 80262, USA. bruce.cuevas@uchsc.edu
Abell
Amy N
AN
Witowsky
James A
JA
Yujiri
Toshiaki
T
Johnson
Nancy Lassignal
NL
Kesavan
Kamala
K
Ware
Marti
M
Jones
Peter L
PL
Weed
Scott A
SA
DeBiasi
Roberta L
RL
Oka
Yoshitomo
Y
Tyler
Kenneth L
KL
Johnson
Gary L
GL
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*
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