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Page 140 Sendino et al. Cancer Drug Resist 2018;1:139-63 I http://dx.doi.org/10.20517/cdr.2018.09

tor in yeast, was identified as the first receptor for the nuclear export of proteins, and it was consequently
[1-4]
renamed exportin 1 (XPO1) . In these initials reports, XPO1/CRM1 (hereafter referred to as XPO1) was
found to be the cellular target for a potent inhibitor of nuclear export termed leptomycin B (LMB), and to
bind short amino acid sequences (so-called nuclear export signals or NESs) in proteins that were actively
exported from the nucleus. Over the last two decades, many aspects of XPO1 physiopathology have been
elucidated. Thus, XPO1 has been shown to mediate the nuclear export of not only hundreds of cellular and
[5,6]
viral proteins, but also of different types of RNA molecules . In fact, crucial signaling pathways, such
as the NF-κB pathway, and essential cellular processes, such as cell cycle progression, have been shown to
[7]
involve XPO1-dependent nuclear export steps . In addition, export-independent functions of XPO1 in
[8]
mitosis have also been identified . The normal function of XPO1 appears to be often disrupted in malig-
nant cells. Thus, overexpression of the XPO1 mRNA or protein has been frequently reported in a variety
of tumor types and recurrent XPO1 gene mutations have been detected in certain hematological malig-
nancies, suggesting that XPO1 may represent a therapeutic target in cancer [9,10] . Importantly, the results of
multiple cellular, biochemical and structural analyses have led to a detailed mechanistic understanding of
XPO1 function [11-13] , paving the way for the development of clinically useful inhibitors of XPO1. Several
compounds targeting XPO1 have been extensively tested in preclinical studies, and one of them, Selinexor,
is now undergoing clinical trials, with promising results in patients with different types of cancer.

THE PHYSIOLOGICAL ROLES OF XPO1
An overview of nucleocytoplasmic transport of proteins
In eukaryotic cells, the nuclear envelope establishes a physical separation between the two major cellular
compartments: the nucleus and the cytoplasm. Cellular homeostasis requires continuous communica-
tion between these compartments through the bidirectional trafficking of molecules. This trafficking
may occur by diffusion in the case of small molecules, or by budding of nuclear envelope-derived vesicles
[14]
for a minority of specific proteins . However, the vast majority of proteins can only enter and exit the
nucleus through proteinaceous channels embedded in the nuclear envelope termed nuclear pore complexes
(NPCs) [15,16] . For most proteins, nucleocytoplasmic transport is an active, energy-dependent process that
requires a specialized transport machinery with three crucial components: (1) the NPCs; (2) a family of
soluble transport receptors (karyopherins) that recognize and bind specific transport signals in the cargo
proteins; (3) a gradient of the small GTPase Ran (bound to either GTP or GDP) across the nuclear enve-
lope, which confers directionality to the transport [Figure 1A] [17-19] .

[15]
[17]
NPCs, recently reviewed by Knockenhauer and Schwartz and Pemberton and Paschal , are very large
complexes (over 120 MDa in size) formed by the assembly of several copies of each of approximately 30 dif-
ferent proteins called nucleoporins (NUPs). NPCs present a characteristic eight-fold rotational symmetry
and are composed by three stacked rings inserted into the nuclear envelope, with a series of filaments ema-
nating to the cytoplasmic side of the NPC and a basket-like structure protruding to the nucleoplasmic side
[Figure 1B]. NUPs in the inner channel of the pore contain intrinsically disordered domains rich in pheny-
alanine-glycine (FG) repeats. These so-called FG-nucleoporins constitute a barrier that efficiently prevents
proteins above a certain size from freely diffusing across the NPC. This threshold size for exclusion has
long been believed to be relatively sharp (30-60 kDa), but a recent study suggests that the NPC lacks such a
firm size threshold . The selective barrier of the NPC can be overcome by large proteins (and even by very
[20]
[21]
large nucleoprotein complexes, such as ribosomal subunits) through binding to karyopherins .
[22]
The human genome codes for approximately 20 different karyopherins . While some of these receptors
can mediate bidirectional transport of cargos in and out of the nucleus, most of them function exclusively
as either import receptors (importins) or export receptors (exportins), such as XPO1. Karyopherins can
recognize and bind specific peptide sequences in the cargo protein, which function as transport signals,
and can be broadly classified as nuclear localization signals (NLSs, recognized by importins) or nuclear