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First published online February 18, 2009
doi: 10.1242/10.1242/jcs.015289

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Ran on tracks – cytoplasmic roles for a nuclear regulator

Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel

View larger version (129K): [in this window] [in a new window]   Fig. 1. Ran-regulated nucleocytoplasmic transport. The model depicts Ran-dependent regulation of nuclear import by importins. A gradient of high RanGTP in the nucleus versus high RanGDP in the cytoplasm is established by nuclear localization of the RanGEF RCC1, and by cytoplasmic localization of RanBP1 (BP1) and RanGAP (GAP), which facilitate displacement and hydrolysis of RanGTP. RanGTP exits the nucleus in a complex with either importin-β (β) or CAS and importin- (). In the cytoplasm, RanGTP encounters RanBP1 and RanGAP, which catalyze its dissociation from the importin complex and hydrolysis to the GDP-bound form. The importins are then free to associate with each other to form a high-affinity carrier for the import of nuclear localization signal (NLS)-containing cargo proteins to the nucleus.

View larger version (75K): [in this window] [in a new window]   Fig. 2. Temporal or transient regulation of the GTP-bound state of Ran controls axonal retrograde signaling in response to injury. (A) Under normal conditions, RanGTP might be generated by a microtubule-bound RanGEF (GEF; see text) and, when bound to axonal CAS and importins, might prevent interaction between importin- and importin-β, as well as the binding of cargo proteins to importins. mRNAs encoding importin β1 (Imp β1) and RanBP1 are found in the axon. (B) Following lesion, Ca2+-dependent localized translation of these mRNAs leads to increased levels of the corresponding proteins, which is thought to occur concomitantly with activation (*) of signaling cargos containing NLS. (C) The newly synthesized RanBP1 (BP1) stimulates both dissociation of RanGTP from the CAS–importin-–dynein complex and RanGAP (GAP)-synergized hydrolysis of RanGTP, thus allowing formation of a cargo-binding complex of importin- with de-novo-synthesized importin-β. Updated and modified from Yudin et al. (Yudin et al., 2008), and reprinted with permission.

View larger version (54K): [in this window] [in a new window]   Fig. 3. Subcellular localization of cytoplasmic RanGEF and RanGAP. The upper panels show localization of the putative GEF RanBP10 on microtubules in megakaryocytes [reprinted with permission from Schulze et al. (Schulze et al., 2008)], and the lower panels show localization and concentration of RanGAP at the tips of growing sensory-neuron axons [reprinted with permission from Yudin et al. (Yudin et al., 2008)]. The juxtaposition of these images (albeit from different cell types) suggests that, if both molecules (or their close homologs) were coexpressed, it might be possible to create localized Ran gradients in the cytoplasm of morphologically complex cells by restricting the amount of GEF to microtubules and that of GAP to other subcellular compartments. NFH, neurofilament heavy chain (a neuronal marker). Scale bars: 15 µm (upper panels; note that the lower panels are not on the same scale).

View larger version (49K): [in this window] [in a new window]   Fig. 4. Is RanBP10 the only cytoplasmic RanGEF? Schematic domain comparisons (A) and sequence alignment (B) of the putative GEF domains suggest that RanBP9 is also a likely RanGEF candidate. In panel B, residues in bold black font are identical in both Ran-binding proteins and a consensus RhoGEF sequence, and residues in blue are identical in RanBP10 and RanBP9. Mutation of the leucine residue shown in red to isoleucine was shown by Schulze et al. (Schulze et al., 2008) to attenuate RanGEF activity of RanBP10.

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