Localized oxidation
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《细胞学杂志》
Despite their bad reputation, free radicals are also beneficial—they are used as second messengers in proliferation, apoptosis, and migration. Oxidants are promiscuous, however, and must be harnessed to modify only specific proteins. One way specificity is achieved in migration, based on findings from Wu et al. (page 893), is by localizing the oxidase with other motility proteins at the leading edge.
Wu and colleagues found that the NADPH oxidase is localized to focal complexes—transient integrin clusters at the front of migrating cells. The oxidase is brought to these sites by the TRAF4 adaptor and Hic5, a paxillin relative.
Disruption of TRAF4–Hic5 interactions that are expected to delocalize the oxidase reduced cell migration, suggesting that the oxidation of a focal complex protein is necessary for motility. This target turns out to be PTP-PEST, a focal complex phosphatase that blocks migration by inactivating the Rac1 GTPase. Phosphatases, including PTP-PEST, are easily inhibited by oxidants, as their catalytic cysteine residues need to be in a reduced state to transfer phosphates.
As oxidation of PTP-PEST activates Rac1, and Rac1 is known to activate the oxidase, the authors have identified a new positive feedback loop that might help amplify shallow gradients of chemoattractants.
This function of TRAF4 in localizing the oxidase might explain why flies and mice mutant in TRAF4 have defects in dorsal and neural tube closure, respectively, as both phenotypes are caused by cell migration failures.(TRAF4 (green) and Hic5 (red) localize th)
Wu and colleagues found that the NADPH oxidase is localized to focal complexes—transient integrin clusters at the front of migrating cells. The oxidase is brought to these sites by the TRAF4 adaptor and Hic5, a paxillin relative.
Disruption of TRAF4–Hic5 interactions that are expected to delocalize the oxidase reduced cell migration, suggesting that the oxidation of a focal complex protein is necessary for motility. This target turns out to be PTP-PEST, a focal complex phosphatase that blocks migration by inactivating the Rac1 GTPase. Phosphatases, including PTP-PEST, are easily inhibited by oxidants, as their catalytic cysteine residues need to be in a reduced state to transfer phosphates.
As oxidation of PTP-PEST activates Rac1, and Rac1 is known to activate the oxidase, the authors have identified a new positive feedback loop that might help amplify shallow gradients of chemoattractants.
This function of TRAF4 in localizing the oxidase might explain why flies and mice mutant in TRAF4 have defects in dorsal and neural tube closure, respectively, as both phenotypes are caused by cell migration failures.(TRAF4 (green) and Hic5 (red) localize th)