Akt phosphorylation of zyxin mediates its interaction with acinus-S and prevents acinus-triggered chromatin condensation.
Zyxin, a focal adhesion molecule, contains LIM domains and shuttles between the cytoplasm and the nucleus. Nuclear zyxin promotes cardiomyocyte survival, which is mediated by nuclear-activated Akt. However, the molecular mechanism of how zyxin antagonizes apoptosis remains elusive. Here, we report that zyxin binds to acinus-S, a nuclear speckle protein inducing apoptotic chromatin condensation after cleavage by caspases, and prevents its apoptotic action, which is regulated by Akt. Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus. Interestingly, 14-3-3gamma, but not zeta isoform selectively, triggers zyxin nuclear translocation, which is Akt phosphorylation dependent. Zyxin is also a substrate of caspases, but Akt phosphorylation is unable to prevent its apoptotic cleavage. Expression of zyxin S142D, a phosphorylation mimetic mutant, diminishes acinus proteolytic cleavage and chromatin condensation; by contrast, wild-type zyxin or unphosphorylated S142A mutant fails. Thus, Akt regulates zyxin/acinus complex formation in the nucleus, contributing to suppression of apoptosis.
Chan
C-B
CB
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Room 145, Whitehead Building, 615 Michael Street, Atlanta, GA 30322, USA.
Liu
X
X
Tang
X
X
Fu
H
H
Ye
K
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D060589:Zyxin
C121310:ACIN1 protein, human; D002843:Chromatin; D003598:Cytoskeletal Proteins; D006023:Glycoproteins; D009687:Nuclear Proteins; C092842:ZYX protein, human; C488370:Zyx protein, rat; D060589:Zyxin; D004815:Epidermal Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases