The RanGTP Pathway: From Nucleo-Cytoplasmic Transport to Spindle Assembly and Beyond

Abstract

The small GTPase Ran regulates the interaction of transport receptors with a number of cellular cargo proteins. The high affinity binding of the GTP-bound form of Ran to import receptors promotes cargo release, whereas its binding to export receptors stabilizes their interaction with the cargo. This basic mechanism linked to the asymmetric distribution of the two nucleotide-bound forms of Ran between the nucleus and the cytoplasm generates a switch like mechanism controlling nucleo-cytoplasmic transport. Since 1999, we have known that after nuclear envelope breakdown (NEBD) Ran and the above transport receptors also provide a local control over the activity of factors driving spindle assembly and regulating other aspects of cell division. The identification and functional characterization of RanGTP mitotic targets is providing novel insights into mechanisms essential for cell division. Here we review our current knowledge on the RanGTP system and its regulation and we focus on the recent advances made through the characterization of its mitotic targets. We then briefly review the novel functions of the pathway that were recently described. Altogether, the RanGTP system has moonlighting functions exerting a spatial control over protein interactions that drive specific functions depending on the cellular context.

Spindle assembly in egg extracts of the Marsabit clawed frog, Xenopus borealis

“…X. tropicalis spindles were also observed to possess distinct morphological features, including more robust kinetochore fibers and a more circular shape (Grenfell et al, ; Loughlin et al, ). Furthermore, whereas spindle assembly in X. laevis extracts required a chromatin‐generated gradient of RanGTP (Cavazza & Vernos, ; Kalab, Weis, & Heald, ), X. tropicalis spindle assembly was not affected by disruption of this pathway (Helmke & Heald, ). Therefore, not only spindle size, but also spindle architecture, morphology, and assembly mechanisms differ between these two species.…”

Restoration of microRNA‐197 expression suppresses oncogenicity in fibrosarcoma through negative regulation of RAN

“…We found RAN (ras‐related nuclear protein) as a direct target for miR‐197‐3p using TargetScan which was validated further by performing qRT‐PCR and dual luciferase reporter assay. RAN is a small GTPase of the RAS superfamily and is involved in several biological processes, such as nucleocytoplasmic transport, nuclear envelope formation, and mitotic spindle assembly . Moreover, overexpression of RAN has already been reported in myriad of cancers, which is also correlated with poor prognosis, increased aggressiveness, and metastasis, inhibition of which can lead to suppression of cancer .…”

“…RAN is a small GTPase of the RAS superfamily and is involved in several biological processes, such as nucleocytoplasmic transport, nuclear envelope formation, and mitotic spindle assembly. [33][34][35] Moreover, overexpression of RAN has already been reported in myriad of cancers, which is also correlated with poor prognosis, increased aggressiveness, and metastasis, [36][37][38] inhibition of which can lead to suppression of cancer. 39 Therefore, to precisely address the oncogenic role of RAN in tumorigenesis of fibrosarcoma, which we found to be upregulated in fibrosarcoma as well.…”

DnaJB6 is a RanGTP-regulated protein involved in dynein-dependent microtubule organization during mitosis

“…In addition to force generation within the spindle, dynein is also essential for 61 focusing microtubule minus--ends into the spindle poles (Echeverri et al,62 RanGTP regulated proteins have been identified and shown to play essential 77 roles in spindle assembly (Cavazza and Vernos, 2015). Recently we used a 78 mass spectrometry based proteomic approach to identify the full proteome 79 associated with RanGTP induced microtubules in Xenopus egg extracts and 80 validated a few selected proteins with no reported function in mitosis (Rosas--81 Salvans et al, 2018).…”