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Promotion of importin alpha-mediated nuclear import by the phosphorylation-dependent binding of cargo protein to 14-3-3.

Faul C, Hüttelmaier S, Oh J, Hachet V, Singer RH, Mundel P - J. Cell Biol. (2005)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

ABSTRACT
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.

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A model for phosphorylation- and 14-3-3-dependent nuclear import of myopodin. (1) When phosphoacceptor sites in 14-3-3–binding motifs#1 (S225) and #2 (T272) are not phosphorylated, myopodin cannot interact with 14-3-3. Therefore, the NLSs in myopodin are not accessible for importin α binding, and myopodin cannot enter the nucleus. (2) After phosphorylation by serine/threonine protein kinases, myopodin binds to 14-3-3, rendering the NLSs accessible for importin α binding. (3) Importin α binds to the NLSs and mediates the nuclear import of myopodin (4).
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fig6: A model for phosphorylation- and 14-3-3-dependent nuclear import of myopodin. (1) When phosphoacceptor sites in 14-3-3–binding motifs#1 (S225) and #2 (T272) are not phosphorylated, myopodin cannot interact with 14-3-3. Therefore, the NLSs in myopodin are not accessible for importin α binding, and myopodin cannot enter the nucleus. (2) After phosphorylation by serine/threonine protein kinases, myopodin binds to 14-3-3, rendering the NLSs accessible for importin α binding. (3) Importin α binds to the NLSs and mediates the nuclear import of myopodin (4).

Mentions: To summarize, this study has helped to identify a functional role for 14-3-3 in promoting nuclear import. In particular, we have shown that importin α binding and the subsequent nuclear import of the tumor suppressor myopodin are regulated by the serine/threonine phosphorylation-dependent binding of myopodin to 14-3-3 (Fig. 6). Altogether, these data provide a novel paradigm for the regulation of nuclear import by 14-3-3 in that 14-3-3 regulates the binding of a phosphorylated cargo protein to importin α and the nuclear import machinery.


Promotion of importin alpha-mediated nuclear import by the phosphorylation-dependent binding of cargo protein to 14-3-3.

Faul C, Hüttelmaier S, Oh J, Hachet V, Singer RH, Mundel P - J. Cell Biol. (2005)

A model for phosphorylation- and 14-3-3-dependent nuclear import of myopodin. (1) When phosphoacceptor sites in 14-3-3–binding motifs#1 (S225) and #2 (T272) are not phosphorylated, myopodin cannot interact with 14-3-3. Therefore, the NLSs in myopodin are not accessible for importin α binding, and myopodin cannot enter the nucleus. (2) After phosphorylation by serine/threonine protein kinases, myopodin binds to 14-3-3, rendering the NLSs accessible for importin α binding. (3) Importin α binds to the NLSs and mediates the nuclear import of myopodin (4).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171942&req=5

fig6: A model for phosphorylation- and 14-3-3-dependent nuclear import of myopodin. (1) When phosphoacceptor sites in 14-3-3–binding motifs#1 (S225) and #2 (T272) are not phosphorylated, myopodin cannot interact with 14-3-3. Therefore, the NLSs in myopodin are not accessible for importin α binding, and myopodin cannot enter the nucleus. (2) After phosphorylation by serine/threonine protein kinases, myopodin binds to 14-3-3, rendering the NLSs accessible for importin α binding. (3) Importin α binds to the NLSs and mediates the nuclear import of myopodin (4).
Mentions: To summarize, this study has helped to identify a functional role for 14-3-3 in promoting nuclear import. In particular, we have shown that importin α binding and the subsequent nuclear import of the tumor suppressor myopodin are regulated by the serine/threonine phosphorylation-dependent binding of myopodin to 14-3-3 (Fig. 6). Altogether, these data provide a novel paradigm for the regulation of nuclear import by 14-3-3 in that 14-3-3 regulates the binding of a phosphorylated cargo protein to importin α and the nuclear import machinery.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus