The Rap family of GTPases are emerging as major regulators of actin dynamics and cell migration. However, how Rap GTPases are activated and targeted to their subcellular localization remains to be fully understood. Recent work has shown that Rab40/CRL5-dependent mono-ubiquitylation is required for Rap2 activation. Here, we show that Rap1 is also mono-ubiquitylated by a Rab40/CRL5 E3 ubiquitin ligase complex and that Rap1 mono-ubiquitylation is necessary for Rap1 localization to both the plasma membrane and nuclear envelope. In summary, this work shows that Rab40/CRL5 is a major regulator of the activity and spatiotemporal dynamics of the Rap family of GTPases.
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