Promotion of importin alpha-mediated nuclear import by the phosphorylation-dependent binding of cargo protein to 14-3-3.
14-3-3 proteins are phosphoserine/threonine-binding proteins that play important roles in many regulatory processes, including intracellular protein targeting. 14-3-3 proteins can anchor target proteins in the cytoplasm and in the nucleus or can mediate their nuclear export. So far, no role for 14-3-3 in mediating nuclear import has been described. There is also mounting evidence that nuclear import is regulated by the phosphorylation of cargo proteins, but the underlying mechanism remains elusive. Myopodin is a dual-compartment, actin-bundling protein that functions as a tumor suppressor in human bladder cancer. In muscle cells, myopodin redistributes between the nucleus and the cytoplasm in a differentiation-dependent and stress-induced fashion. We show that importin alpha binding and the subsequent nuclear import of myopodin are regulated by the serine/threonine phosphorylation-dependent binding of myopodin to 14-3-3. These results establish a novel paradigm for the promotion of nuclear import by 14-3-3 binding. They provide a molecular explanation for the phosphorylation-dependent nuclear import of nuclear localization signal-containing cargo proteins.
Faul
Christian
C
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Hüttelmaier
Stefan
S
Oh
Jun
J
Hachet
Virginie
V
Singer
Robert H
RH
Mundel
Peter
P
D048948:14-3-3 Proteins / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D032446:Myoblasts / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D028901:alpha Karyopherins / Q000378:metabolism*
D048948:14-3-3 Proteins; D008840:Microfilament Proteins; C503979:SYNPO2 protein, human; C503980:Synpo2 protein, mouse; D028901:alpha Karyopherins