Research ArticleCell Biology

The subcellular localization and activity of cortactin is regulated by acetylation and interaction with Keap1

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Sci. Signal.  24 Nov 2015:
Vol. 8, Issue 404, pp. ra120
DOI: 10.1126/scisignal.aad0667

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Acetylation against cell migration

The actin-binding protein cortactin promotes cell migration through cytoskeletal remodeling in the cell cortex and is abundant in certain types of aggressive cancers. Ito et al. found that the cytosolic protein Keap1 promoted the localization of cortactin to the cell cortex and thus cell migration. Cortactin shuttled between the cytoplasm and the nucleus; however, upon acetylation, cortactin no longer bound to Keap1 and became predominantly localized in the nucleus. Thus, increasing the acetylation of cortactin or preventing it from binding to Keap1 may suppress the metastasis of cancer cells.

Abstract

Cortactin is an F-actin–binding protein that localizes to the cell cortex, where the actin remodeling that is required for cell migration occurs. We found that cortactin shuttled between the cytoplasm and the nucleus under basal conditions. We identified Kelch-like ECH-associated protein 1 (Keap1), a cytosolic protein that is involved in oxidant stress responses, as a binding partner of cortactin that promoted the cortical localization of cortactin and cell migration. The ability of cortactin to promote cell migration is regulated by various posttranslational modifications, including acetylation. We showed that the acetylated form of cortactin was mainly localized to the nucleus and that acetylation of cortactin decreased cell migration by inhibiting the binding of cortactin to Keap1. Our findings reveal that Keap1 regulates cell migration by affecting the subcellular localization and activity of cortactin independently of its role in oxidant stress responses.

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