RANBP1 (RAN Binding Protein 1): The Missing Genetic Piece in Cancer Pathophysiology and Other Complex Diseases

SIMPLE SUMMARY: In just less than 30 years since the cloning of RANBP1 (RAN binding protein 1), this review represents the first attempt for a comprehensive and analytical compilation of the main works that have characterized the history of this gene. Originally defined as an accessory element of not well-defined proteins involved in nuclear transport, RANBP1 has been demonstrated, over time, to play an essential role in maintaining both nuclear import/export machinery and spindle check-point formation. Since the first biochemical characterization, knowledge has accumulated that paints a very complex picture of how RANBP1 and its Small-GTPase-related complex plays a fine regulation of cellular homeostasis, with a differentially phase-cell-dependent role. From its molecular context, up to the role in neoplastic and other pathologies of complex traits, RANBP1 always embodies further the missing piece of a gene signature that recapitulates several aspects of mammalian cell biology. ABSTRACT: RANBP1 encoded by RANBP1 or HTF9A (Hpall Tiny Fragments Locus 9A), plays regulatory functions of the RAN-network, belonging to the RAS superfamily of small GTPases. Through this function, RANBP1 regulates the RANGAP1 activity and, thus, the fluctuations between GTP-RAN and GDP-RAN. In the light of this, RANBP1 take actions in maintaining the nucleus–cytoplasmic gradient, thus making nuclear import–export functional. RANBP1 has been implicated in the inter-nuclear transport of proteins, nucleic acids and microRNAs, fully contributing to cellular epigenomic signature. Recently, a RANBP1 diriment role in spindle checkpoint formation and nucleation has emerged, thus constituting an essential element in the control of mitotic stability. Over time, RANBP1 has been demonstrated to be variously involved in human cancers both for the role in controlling nuclear transport and RAN activity and for its ability to determine the efficiency of the mitotic process. RANBP1 also appears to be implicated in chemo-hormone and radio-resistance. A key role of this small-GTPases related protein has also been demonstrated in alterations of axonal flow and neuronal plasticity, as well as in viral and bacterial metabolism and in embryological maturation. In conclusion, RANBP1 appears not only to be an interesting factor in several pathological conditions but also a putative target of clinical interest.