RanGTP

RanGTP is the GTP-bound form of the small GTPase Ran, a member of the Ras superfamily. It functions as a central regulator of nucleocytoplasmic transport and, in many cells, of spindle assembly during mitosis. The GTP-bound state of Ran interacts with transport receptors and cargo to direct their movement between the nucleus and cytoplasm.

The Ran cycle is driven by two regulators. In the nucleus, the guanine nucleotide exchange factor RCC1 converts RanGDP to RanGTP, creating a high nuclear RanGTP concentration. In the cytoplasm, RanGAP stimulates GTP hydrolysis to RanGDP, maintaining a high cytoplasmic pool of RanGDP. The resulting RanGTP gradient provides directionality for transport processes across the nuclear pore complex.

Cargo movement relies on karyopherins, including importins and exportins. In the cytoplasm, cargo bearing a nuclear localization signal binds importin and is transported into the nucleus; inside the nucleus, RanGTP binds importin and induces cargo release. For export, cargo bearing a nuclear export signal forms a complex with exportin and RanGTP in the nucleus; after translocation to the cytoplasm, RanGTP is hydrolyzed, releasing cargo.

In mitosis, a chromatin-associated RanGTP gradient promotes spindle assembly by activating spindle assembly factors and regulating microtubule dynamics, a mechanism that operates even when the nuclear envelope breaks down.

Regulation and significance: RanGTPase activity is tightly controlled by RCC1, RanGAP, and effector proteins such as RanBP1. Proper RanGTP cycling is essential for accurate nucleocytoplasmic transport and chromosome segregation; disruptions can lead to cellular defects and are studied for potential therapeutic implications.