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KPNB1 (karyopherin (importin) beta 1)

Written2013-04Maria Giubettini, Pauline van der Watt, Annalisa Verrico, Valeria de Turris, Virna Leaner, Patrizia Lavia
CNR (National Research Council), Institute of Molecular Biology, Pathology, c/o Sapienza University of Rome, via degli Apuli 4, 00185 Rome, Italy (MG, AV, VDT, PL); Division of Medical Biochemistry, Faculty of Health Sciences, Institute of Infectious Disease, Molecular Medicine, University of Cape Town, South Africa (PVDW, VL)

(Note : for Links provided by Atlas : click)

Identity

Alias_nameskaryopherin (importin) beta 1
Alias_symbol (synonym)NTF97
IPOB
MGC2155
MGC2156
MGC2157
IMB1
Impnb
IPO1
Other alias
HGNC (Hugo) KPNB1
LocusID (NCBI) 3837
Atlas_Id 41101
Location 17q21.32  [Link to chromosome band 17q21]
Location_base_pair Starts at 47651196 and ends at 47683638 bp from pter ( according to hg19-Feb_2009)  [Mapping KPNB1.png]
Fusion genes
(updated 2016)
CDCP1 (3p21.31) / KPNB1 (17q21.32)KPNB1 (17q21.32) / ACE (17q23.3)KPNB1 (17q21.32) / KALRN (3q21.2)
KPNB1 (17q21.32) / KPNB1 (17q21.32)KPNB1 (17q21.32) / LSM4 (19p13.11)KPNB1 (17q21.32) / MDH1 (2p15)
KPNB1 (17q21.32) / NPEPPS (17q21.32)KPNB1 (17q21.32) / S100A13 (1q21.3)KPNB1 (17q21.32) / SKAP1 (17q21.32)
KPNB1 (17q21.32) / ZNF595 (4p16.3)PITPNM2 (12q24.31) / KPNB1 (17q21.32)RALY (20q11.22) / KPNB1 (17q21.32)
TTR (18q12.1) / KPNB1 (17q21.32)

DNA/RNA

 
  Figure 1. Adapted from Cosmic.
Description The KPNB1 gene is constituted of 34163 bp of DNA.
Transcription The transcript variant 1 mRNA (4276 bp) contains 20 exons encoding Importin beta 1 (source: NCBI; nucleotide sequences: GenBank L39793, EMBL-Bank, DDBJ, RefSeq: NM_002265, CCDS: CCDS11513.1, Vega: OTTHUMG00000036957).

Protein

Note Biological overview: Importin beta 1 is a prominent member of the karyopherin beta family of transport receptors (reviewed by Ström and Weis, 2001; Mosammaparast and Pemberton, 2004; Chook and Süel, 2011). It was originally identified as an indispensable component for nuclear import of proteins that function in the nucleus of interphase cells (Moore and Blobel, 1992; Adam and Adam, 1994; Radu et al., 1995; Görlich et al., 1995). Due to the importance of nuclear transport of proteins (e.g. DNA replication and repair factors, transcription factors, epigenetic regulators, hormone receptors, oncogenes and tumor suppressors; see Fulcher and Jans, 2011), that discovery was awarded the Nobel prize for Biomedicine to Prof. Günter Blobel in 1999 (www.nobelprize.org/nobel_prizes/medicine/laureates/1999/blobel-lecture.html).
The discovery of importin beta 1 as a nuclear import vector overshadowed other functions for some time, but it is now well recognized that importin beta 1 plays multiple roles in cell life and division beyond nucleo-cytoplasmic transport, as will be explained in more depth below:
- at mitotic onset nucleo-cytoplasmic transport ceases and importin beta 1 assumes new functions as an inhibitor of mitotic factors with which it interacts and participating in many mitotic steps (see below). Because these factors are not biologically productive when bound to importin beta 1, the latter is regarded as a negative regulator of mitotic progression (reviewed by Ciciarello et al., 2007; Kalab and Heald, 2008);
- Importin beta 1 also regulates the reorganization of the nucleus and the nuclear envelope at mitotic exit prior to the resumption of nucleo-cytoplasmic transport in the next interphase (reviewed by Harel and Forbes, 2004; Güttinger et al., 2009); in this processes it largely operates via nuclear envelope precursors and nucleoporins (NUP), the constituents of nuclear pore complexes (NPCs) that fenestrate the nuclear envelope.
Importin beta 1 is therefore a versatile regulator of critical importance to many essential cellular processes and is growingly implicated in the onset of genomic instability in cells in which it is expressed in a deregulated manner.
Description The human importin beta 1 protein is composed of 876 aminoacidic residues, with a molecular weight of 97 kDa (Görlich et al., 1995; Chi et al., 1995). It contains 19 HEAT repeats arranged in a superhelical spiral. Each HEAT repeat (about 40-60 aminoacids) consists of A and B helices connected by a short turn, with the A helices localizing to the importin beta 1 outer surface, and the B helices in the inner surface (Cingolani et al., 1999).
Importin beta 1 has a modular flexible structure that enables it to interact with distinct partners in different subcellular compartments in interphase cells, such that each module or domain has a 'topologically' specialized function (reviewed by Ström and Weis, 2001; Conti et al., 2006):
- an extended C-terminal region of importin beta 1 contains sites of interaction with members of the importin alpha subfamily transport receptors (Importin alpha-binding domain, IAB), through which importin beta 1 interacts indirectly with import cargoes (Percipalle et al., 1997; Cingolani et al., 1999). The IAB domain is essential for the formation of import complexes in the cytoplasm, where proteins are synthesized;
- the central region of importin beta 1 contains two major binding sites for phenyl-glycine (FG and FXFG)-rich repeats present in nucleoporins (NUPs), the constituents of nuclear pores (Bayliss et al., 2000; Bayliss et al., 2002; Bednenko et al., 2003); that interaction enables the import complex to traverse the NPC (Ben-Efraim and Gerace, 2001). Studies with importin beta 1 truncated mutants have mapped the two NUP-binding sites respectively in the N-terminal portion (between HEATs 5 and 7) (Kutay et al., 1997; Chi and Adam, 1997; Bednenko et al., 2003), and near the C-terminal domain (between HEATs repeats 14 and 16; Bednenko et al., 2003) of the central region;
- the N-terminal region of importin beta 1, termed CRIME (for CRM1, Importin beta, etc.), harbours a highly conserved sequence among transport receptors, capable of interacting with the GTP-bound form of the GTPase RAN, which is generated in the nucleus. RANGTP binding to the CRIME domain dissociates the import complex and releases free protein cargoes in the nucleus (Kutay et al., 1997; Vetter et al., 1999).
Importin beta 1 crystals and three-dimensional structures are solved for all domains involved in these interactions (Vetter et al., 1999; Bayliss et al., 2000; Bayliss et al., 2002; Cingolani et al., 1999, Cingolani et al., 2002; Bednenko et al., 2003; Saric et al., 2007; PDB). Structural studies have been essential to clarify that importin beta 1 interacts in a mutually exclusive manner with either importin alpha, or with RANGTP (Moroianu et al., 1996); this provides the structural basis for the formation of import complex in the cytoplasm (devoid of RANGTP) and for import complex dissociation and cargo release in the nucleus (rich of RANGTP).
Expression Although most importin family members are constitutively expressed, emerging evidence shows that expression of at least some importin-coding genes is regulated (Zhang et al., 2000; Hogarth et al., 2006), possibly to adapt to varying requirements for interphase nucleocytoplasmic transport and mitotic division e.g. in development (Vrailas et al., 2006).
The importin beta 1 gene is thought to be expressed in a housekeeping, ubiquitous manner in human tissues, yet has highest expression in actively proliferating tissues, e.g. lymphocytes, tumors, testis and undifferentiated cells (Quan et al., 2008). Elevated importin beta 1 expression in some cancer cell lines has recently been demonstrated to reflect increased transcription due to deregulated activity of the E2F/pRb pathway, involving the transcriptional factor E2F and the Retinoblastoma tumor suppressor protein (van der Watt et al., 2011).
 
  Figure 2. Localization of importin beta 1 by immunofluorescence, in a human HeLa cell in interphase. Importin beta 1 (red) accumulates in the nucleus and around the nuclear envelope, with a regular, punctuate pattern, typical of the association with nuclear pores. The nucleus is visualized by staining the DNA with 4',6-diamidino-2-phenylindole (DAPI, blue) and the cell shape is depicted by staining the cytoskeleton using an antibody against alpha-tubulin (green). Bar: 5 μM.
Localisation The localization of importin beta 1 protein is related to its function. In interphase, when it acts in nuclear import of proteins, it is particularly abundant at the nuclear envelope, with a punctuate pattern corresponding to NPCs (figure 2). This localization is particularly evident after treatment with mild detergents that remove soluble importin beta 1.
At mitotic onset, when the nuclear envelope breaks down, importin beta 1 associates with mitotic microtubules, as determined in co-sedimentation assays; importin alpha also co-sediments with mitotic microtubules. The association of both importins alpha and beta 1 with the mitotic spindle microtubules requires the minus end-directed motor dynein (figure 3; Ciciarello et al., 2004). Due to the minus-end directed movement of dynein, the importin alpha/beta dimer can transport NLS-containing spindle regulatory factors to the poles, and thus regulate the mitotic apparatus organization and function.
By immunofluorescence staining, importin beta 1 co-localizes with the mitotic spindle and accumulates to the spindle poles (figure 4, top and midde rows), consistent with the microtubule association assay (figure 3). In early telophase, when chromosome segregation is complete, importin beta 1 dissociates from the microtubules and relocalizes around the reforming nuclei (Ciciarello et al., 2010; figure 4 bottom row).
 
  Figure 3. Sedimentation assay of mitotic microtubules (MTs) after centrifugation through a sucrose gradient; tubulin monomers and dimers remain in the supernatant. Microtubule-associated proteins were analyzed by Western immunoblotting of the MT pellet, revealed by alpha-tubulin antibody. As schematized on the right, ATP addition recovers proteins that associate with MTs directly: under these circumstances, no importin beta 1 signal is detected in the MT pellet (Western panel, lane 2). The addition of non-hydrolyzable AMPPnP analogue recovers proteins that associate with MTs via motors: under these conditions, both importin beta 1 and importin alpha co-sediment with the MT pellet, as does the mitotic kinase p34/cdk1 (lane 1). To identify the specific motor protein that bridges importin alpha and beta 1 to mitotic MTs, the pellet was incubated with antibody to the dynein intermediate chain (anti-DIC), which sequesters dynein: under these conditions, importin alpha and beta 1 detach from the MT pellet (lanes 4), as does dynamitin, whereas a non-specific IgM has no effect (lane 3). These assays indicate that importin alpha and beta 1 interact with mitotic MTs via dynein. Details in Ciciarello et al., 2004.
Function Importin beta 1 is required for cell survival. RNA interference assays to analyse the requirement for single importin family members in HeLa cells (Quensel et al., 2004) showed that importin beta 1 could not be fully silenced after prolonged RNA interference (seven days), implying that it is very stable at either the mRNA or the protein levels. Moreover, after interference, importin beta 1 showed the weakest reduction in abundance compared to all other tested importins alpha types, suggesting that cells are less tolerant to the loss of importin beta 1 compared to any other member, such that cells in which importin beta 1 was effectively silenced were counterselected. Indeed, importin beta 1 downregulation caused a significant decrease in the number of viable cells, with significant induction of cell death (Quensel et al., 2004).
Importin beta 1 as the universal vector for interphase nuclear import
As recalled above, the first identified function of importin beta 1 was protein import in interphase cell nuclei (Görlich and Kutay, 1999). Most proteins that function in the nucleus carry one or more nuclear localization signal (NLS, short stretches of charged aminoacidic residues), recognized by a member of the importin alpha subfamily of transport receptors (adaptors), that interact with importin beta 1 through the IAB domain. Importin beta 1 can heterodimerise with different proteins of the importin alpha subfamily that confer specificity in binding cargoes with subtle NLS sequence variations. This leads to the formation of a trimeric complex (NLS cargo/importin alpha/importin beta) in the cytoplasm (classical nuclear import pathway). Importin beta 1 can also interact with particular cargoes directly, without the mediation of an importin alpha adaptor ("direct" import pathway); the latter is faster yet more uncommon than the classical heterodimer-mediated pathway (Harel and Forbes, 2004; Riddick and Macara, 2007). Most protein cargoes, many of which are relevant to cancer (e.g. c-Myc, pRb, others listed in Marfori et al., 2011), are imported through an importin alpha adaptor, and some through direct interaction with importin beta 1 (e.g. cyclin B1, Smad3, c-Jun, PP2A; other examples in Chook and Süel, 2011). Importin beta 1 also binds Snurportin 1 as an adaptor that binds the m3G-cap of small nuclear RNAs (snRNAs) to import snRNPs (Mitrousis et al., 2008).
Once the classical or direct import complex assembles in the cytoplasm, importin beta 1 drives its translocation across the nuclear pore into the nucleus. Importin beta 1 is thought to traverse the NPC by alternating the binding of its NUP-binding domain to different NUPs, positioned in different NPC regions and endowed with progressively increasing affinity for importin beta 1 from the cytoplasm towards the nucleoplasm (Ben-Efraim and Gerace, 2001).
Upon entry in the nucleus, the GTPase RAN, which is abundant in the nucleus in the GTP-bound form, interacts with the importin beta 1 CRIME domain; this interaction dissociates the import complex and releases free, biologically productive protein cargoes in the nucleoplasm, thus terminating the import process. RANGTP and importin beta 1 exit the nucleus together as a complex and dissociate in the cytoplasm (where RANGTP is hydrolyzed to RANGDP), such that a novel import cycle can restart.
Importin beta 1 as a global regulator of mitosis
Importin beta 1 plays key roles in mitosis. For clarity, we will separately summarize importin beta 1 roles in a) mitotic spindle assembly and spindle pole formation, b) microtubule/kinetochore interactions and chromosome segregation, c) progression to mitotic completion, and d) mitotic exit.
a) Regulation of mitotic spindle assembly. Early indications that importin beta 1 regulates mitotic spindle formation came from studies with Xenopus oocyte-derived extract systems, a classical model for spindle assembly due to its high content of spindle assembly factors (SAFs). The simple addition of importin beta 1 to the extract was found to preclude the formation of the mitotic spindle, but RANGTP addition reversed the inhibition (Wiese et al., 2001; Nachury et al., 2001). This lead to a simple model, in which importin beta 1 inhibits the SAFs that interact with it, whereas RANGTP releases SAFs in a free, biologically active form with the same mechanisms operating in the classical import pathway. Indeed, two major spindle organizers, i.e. TPX2 (targeting protein for Xklp2; Gruss et al., 2001) and NuMA (Nuclear and mitotic apparatus protein, Wiese et al., 2001; Nachury et al., 2001), both contain NLS signals and are therefore sensitive to importin beta 1-dependent inhibition.
The spindle inhibitory role of importin beta 1 is conserved across species, in spite of significant biological differences between female germ cell-derived meiotic systems (acentrosomal systems, in which the spindle formation is driven by microtubules originating from a small chromatin volume, standing out as a discrete entity within a large cytoplasm) and mammalian somatic mitotic cells (where the spindle microtubules are predominantly nucleated from centrosomes, with a small contibution from kinetochore-originating microtubules O'Connell and Khodjakov, 2007). Importin beta 1 microinjection in Ptk1 rat-kangoroo cells caused the formation of aberrant, multipolar spindles and defective chromosome alignment, attributable to NuMA inhibition (Nachury et al., 2001). Importin beta 1 overexpression also yielded multipolar spindles with fragmented poles in human HeLa cells, such that chromosome could not congress along a bipolar axis at metaphase (Ciciarello et al., 2004; Kalab et al., 2006). Co-expression of exogenous TXP2, or of any NLS sequence, restored bipolar spindle formation, presumably by "titrating out" the inhibitory effect of importin beta 1 (Ciciarello et al., 2004). Importin beta 1 also suppresses the microtubule-nucleation potential of kinetochores in human cells (Tulu et al., 2006; Torosantucci et al., 2008; O'Connell et al., 2009).
Several more microtubule-regulatory factors involved in spindle formation or function were subsequently found to be inhibited when importin beta 1 binds them, either directly or indirectly, e.g.: the microtubule minus-end binding factor MCRS1 (Meunier and Vernos, 2011); the kinesin XCTK2 (Ems-McClung et al., 2004); the chromokinesin Kid (Trieselmann et al., 2003; Tahara et al., 2008); the CRB3 member of the Crumbs transmembrane protein family, that binds the membrane compartment of cilia and spindle poles (Fan et al., 2007); maskin, a member of the TACC (transforming acidic coiled coil) protein family (Albee et al., 2006); the microtubule-binding proteins NuSAP (Nucleolar and spindle-associated protein; Ribbeck et al., 2006), HURP (hepatoma up-regulated protein; Silljé et al., 2006) and Xnf7 (Maresca et al., 2005); Rae 1, an RNA-binding and mitotic spindle-associated factor (Blower et al., 2005). Many of these factors are implicated in generating genomic instability in cancer cells and the list is growing. These studies indicate that importin beta 1 physiologically inhibits the unscheduled, premature or ectopic activity of mitotic spindle factors until RANGTP reverses the inhibition. Thus, importin beta and RANGTP ensure temporal and spatial control of spindle formation with the same mechanisms operating in protein nuclear import.
b) Chromosome congression, alignment and segregation. Once the mitotic spindle is assembled, importin beta 1 regulates kinetochore functions and attachment to microtubules. These functions do not necessarily involve import-type complexes with NLS factors: indeed, assay of importin beta 1 truncated mutants showed that the NUP-binding domain alone can inhibit these processes in a dominant negative manner, while the IAB and NLS-interacting domain is dispensable for these effects (Roscioli et al., 2012). This role is associated with the regulated delivery of a complex comprising NUP358-RANBP2, a large NUP with SUMO E3 ligase activity, and SUMO-conjugated RANGAP1, to kinetochores (Roscioli et al., 2012). SUMO conjugation to RANGAP1 requires RANBP2 (Joseph et al., 2002; Joseph et al., 2004), with which importin beta 1 interacts along the spindle microtubules (Roscioli et al., 2012). In a normal mitotic progression, a fraction of RANBP2 and SUMO-conjugated RANGAP1 are recruited to kinetochores when the latter attach to microtubules (Joseph et al., 2002; Joseph et al., 2004) in a process requiring CRM1. The process ultimately modifies the RAN status at kinetochores and is important for kinetochore maturation and stable attachment to microtubules during chromosome segregation (Arnaoutov and Dasso, 2003). Importin beta 1 overexpression inhibits the process (Roscioli et al., 2012), suggesting that its physiological role is to prevent premature RANGAP1 delivery, and hence premature RANGTP hydrolysis, to kinetochores. Importin beta 1-dependent negative control also applies to the kinetochore localization of CENP-F, a factor involved in stabilization of microtubule/kinetochore interactions (Roscioli et al., 2012).
c) Mitotic completion. When chromosome segregation begins, timely waves of proteolysis eliminate factors required in early mitotic stages, such that the cell can progress towards mitotic completion. Some importin beta 1-interacting proteins required for spindle function and microtubule stabilization, i.e. HURP and NuSAP, are among substrates of the Anaphase-Promoting Complex, an E3 ubiquitin ligase that targets cell cycle proteins for degradation by the 26S proteasome. Their degradation requires release from importin beta 1 by RANGTP: thus, importin beta 1 regulates mitotic progression by regulating the timely degradation of key spindle factors (Song and Rape, 2010).
Additional evidence implicates importin beta 1 in progression through late mitosis: indeed, the Repo-Man protein, which recruits the phosphatase PP1-γ onto mitotic chromatin at anaphase and participates to histone dephosphorylation, targets importin beta 1 as well as other proteins (e.g. NUP153, the most distal NUP on the NPC nuclear side) to anaphase chromatin (Vagnarelli et al., 2011). This binding occurs via direct interaction between Repo-Man and importin beta 1. Repo-Man binding to the chromosome periphery is thought to provide anchoring sites for importin beta 1, potentially marking sites where NPCs will eventually reassembly.
Further evidence indicate an intriguing link between importin beta 1 and protein phosphatases at mitotic completion. A high-throughput RNA interference screening in HeLa cells identified the PP2A phosphatase as a major regulator of mitotic spindle disassembly and nuclear import resumption (Schmitz et al., 2010). Noteworthily, importin beta 1 is part of a complex with PP2A; importin beta 1 depletion by RNA interference delayed the anaphase-G1 transition and hindered mitotic exit. Thus, PP2A and importin beta 1 cooperate in regulation of post-mitotic processes presumably via regulated dephosphorylation of key substrates in late mitotic stages.
d) Mitotic exit and nuclear reformation. When cells exit mitosis, importin beta 1 regulates the reformation of a functional nuclear envelope fenestrated by NPCs in order to reestablish nucleocytoplasmic transport and, hence, nuclear localization of transcription, epigenetic and regulatory factors in the following cell cycle. Importin beta 1 detaches from microtubules in late anaphase/early telophase: at this point, the microtubules reorganize to form the midbody while importin beta 1 relocalizes around the periphery of the decondensing chromatin (Ciciarello et al., 2010; figure 4) and regulates critical processes therein:
- human importin beta 1 protein addition to a Xenopus nuclear reconstitution system negatively regulates both the membrane fusion events required for reorganizing the double-layered nuclear envelope around chromatin (RANGTP-reversible), and the assembly of NPCs into fused nuclear membranes (not reversible by RAN and involving FG-containing NUPs) (Harel et al., 2003). Using a similar approach Rotem et al. found that importin beta 1 forms a high-molecular-weight complex with NUP107-160 (a subcomplex of the NPC comprising eight NUPs), and ELYS, an adaptor between the NUP107-160 complex and chromatin; when added in excess, importin beta 1 inhibits NUP107-160/ELYS complex binding to chromatin, yielding abnormal nuclei with aberrantly organized, non functional envelopes (Rotem et al., 2009).
- importin beta 1 also regulates the repositioning of NUPs around the decondensing chromatin in intact mammalian telophase cells (Ciciarello et al., 2010). Lu et al. reported that in human HeLa cells importin beta 1 interacts with the lamin B receptor, a chromatin- and lamin B-binding protein in the inner nuclear membrane, and that this interaction targets membrane precursor vesicles to chromatin at mitotic exit (Lu et al., 2010).
To sum up, importin beta 1 is a multifunctional regulator, acting at diverse stages of mitosis with specificity:
- in space (at the mitotic spindle microtubules and poles, at the microtubule-kinetochore interface and around the decondensing chromatin);
- in time (spindle formation in early mitosis, microtubule stability and attachment to kinetochores at metaphase, chromosome segregation in late mitosis, mitotic completion and transition to the next interphase);
- in target selectivity (NLS-containing factors, via formation of import-type complexes; NUPs, as well as some microtubule regulators and some protein phosphatases, via direct interaction).
Although we do not yet fully know which specific regulatory switches underlie these diversfied functions of importin beta 1 during mitotic progression, it is clear that a common theme is the intracellular abundance of importin beta 1 over its target factors, which is critical to the correct unfolding of all mitotic processes in which importin beta 1 participates. Through these activities, importin beta 1 can contribute to determine mitotic errors and genomic instability in cells in which it is expressed in a deregulated manner.
 
  Figure 4. Importin beta 1 localization in human HeLa cells during mitotic progression. Importin beta 1 (red) accumulates at mitotic spindle microtubules and poles until anaphase; later in telophase it relocalizes around the segregating chromatin, where the nuclear envelope will reform. An antibody against alpha-tubulin (green) stains the spindle microtubules and the midbody in telophase. DAPI stains chromosomes. The merged pictures represent the overlay of all three images. Bars: 5 μm.
Homology Human importin beta 1 belongs to the karyopherin beta family of nuclear transport factors, within which 15 evolutionarily derived subfamilies can be distinguished according to their Uniprot gene names (Quan et al., 2008; Chook and Süel, 2011; O'Reilly et al., 2011). Karyopherin beta family members share similar molecular weights (90-150 kDa) and isoeletric points (pI: 4.0-5.0), low sequence identity (10-20%) but all contain helical HEAT repeats.
The kariopherin beta family is highly conserved across Eukaryota, from Saccharomyces cerevisiae (14 members) to humans (19 members), suggesting conservation of basic transport mechanisms, though with adaptation to specific cellular / organism contexts (Chook and Süel , 2011; O'Reilly et al., 2011) and orthologs have been identified in Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, Xenopus tropicalis, Gallus gallus, and Mus musculus (Quan et al., 2008). Remarkably, there is higher homology between orthologues across species than between paralogues in the same species (Quan et al., 2008). In particular, human importin beta 1 belongs to the IMB1 subfamily, named Kap95p in Saccharomyces cerevisiae (Chook and Süel, 2011; O'Reilly et al., 2011) and orthologs have been identified in Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, Xenopus tropicalis, Gallus gallus, and Mus musculus (Quan et al., 2008).

Mutations

Note No spontaneous mutations are reported in human cells or tissues. Importin beta 1 mutants (i.e. point mutations or deletion mutants) have been engineered in several laboratories to study the role of different domain in various cellular processes.

Implicated in

Note
  
Entity Cervical cancer
Note Cervical cancer is the second most common cancer among women worldwide. Importin beta 1 is overexpressed in cervical cancer patient specimens and cell lines, often in combination with CRM1, and is critical for cancer cell survival and proliferation (van der Watt et al., 2009). Gene expression profiling in normal and cervical cancer biopsies by microarray analysis and quantitative RT-PCR revealed highly significant overexpression of importin beta 1 compared to normal cervical tissue (p< 0.0005). By immunofluorence on tissue sections, importin beta 1 protein abundance was confirmed to be higher compared to healthy specimens (p<0.05). Moreover, importin beta 1 inhibition by RNA interference in a panel of cervical cancer cell lines (CaSki, Hela, SiHa, MS751 and C33A) reduced cell proliferation leading to cell death (increase of sub-G1 population and apoptosis), coupled with an increase in the level of growth-inhibitory and tumor-suppressor proteins, i.e. p53, p21, p27 and p18, suggesting that these proteins are part of the apoptotic response in importin beta 1 knock-down cells.
The same group also demonstrated that elevated importin beta 1 expression in cervical cancer correlates with altered transcriptional regulation, associated with deregulated activity of E2F/pRb (retinoblastoma) pathway (van der Watt et al., 2011). Promoter elements required for high importin beta 1 transcription in transformed and cervical cancer cells map to the -637 to -271 importin beta 1 promoter region. Bioinformatic analysis of this region identified five putative binding sites for E2F, three of which were proved to be functional in site-directed mutagenesis assays (van der Watt et al., 2011). E2F activity is well-known to be deregulated in cervical cancer cells due to inactivation of its negative control partner, pRb, by the E7 oncoprotein of HPV, leading to deregulated expression of pRb target genes.
In summary, the E2F sites in the importin beta 1 gene promoter up-regulate importin beta 1 transcription, largely due to E7-dependent inhibition of pRb, and E2F-dependent promoter activation is more pronounced in transformed and cancer compared to normal cells.
  
  
Entity Ovarian cancer
Note Importin beta 1 mRNA and protein levels are elevated in ovarian cancer cell lines and transformed ovarian cells compared to normal primary ovarian epithelial cells (Smith et al., 2010).
  
  
Entity Transformed fibroblasts
Note Importin beta 1 protein levels are higher in transformed fibroblast cell lines (SVWI38 and CT-1) compared to normal fibroblasts (WI38), suggesting that up-regulation of importin beta 1 is not confined to cervical cancer and may be associated with cellular transformation in general (van der Watt et al., 2009).
  
  
Entity Other cancer types
Note Increased levels of importin beta 1 are found in several transformed cells lines compared to their respective untransformed counterparts, and these increased importin beta 1 levels contribute towards increased rates of nuclear import in transformed cells (Kuusisto et al., 2012). A genome-wide siRNA screen identified importin beta 1 as a gene necessary for the survival of both lung and head and neck cancer cell lines, highlighting its importance in cancer cells (Martens-de Kemp et al., 2013). Other instances of cancer tissue profiling of particular cancer types, in which importin beta 1 is differentially expressed (i.e. overexpressed or underexpressed) compared to matched non cancer samples are listed in Rensen et al. 2008. More recent datasets illustrating differential expression in cancer can be found in www.oncomine.org.
  

To be noted

The association of importin beta 1 with cancer is reviewed in van der Watt et al. 2013, and importin beta 1 is implicated as a potentially useful anti-cancer target (van der Watt et al., 2013). Moreover, since importin beta 1 inhibition prevents the nuclear localization of its numerous cargo proteins, this could hypothetically be exploited for therapeutic purposes. For example, its inhibition prevents the nuclear translocation of death receptor 5 (DR5), thereby increasing the sensitivity of cancer cells to TRAIL-induced cell death (Kojima et al., 2011).
In synthesis, the potential of importin beta 1 in generating genomic instability in cancer development, and, when dramatically down-regulated, in mislocalizing regulators of cell death, has generated increasing interest in the design of selective inhibitors. Karyostatin 1A, a small molecule that binds importin beta 1, has been described to specifically inhibit importin α/β nuclear import by disrupting the interaction between importin beta 1 and RAN (Hintersteiner et al., 2010). A more recent study has led to the synthesis of a specific importin beta 1 small molecule inhibitor, called importazole, designed to alter the interaction with RANGTP, with potential for studies of the RAN pathway and for possible therapeutic applications (Soderholm et al., 2011).

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Mol Biol Cell. 1997 Jun;8(6):945-56.
PMID 9201707
 
Nuclear import by karyopherin-betas: recognition and inhibition.
Chook YM, Suel KE.
Biochim Biophys Acta. 2011 Sep;1813(9):1593-606. doi: 10.1016/j.bbamcr.2010.10.014. Epub 2010 Oct 26. (REVIEW)
PMID 21029754
 
Nuclear reformation after mitosis requires downregulation of the Ran GTPase effector RanBP1 in mammalian cells.
Ciciarello M, Roscioli E, Di Fiore B, Di Francesco L, Sobrero F, Bernard D, Mangiacasale R, Harel A, Schinina ME, Lavia P.
Chromosoma. 2010 Dec;119(6):651-68. doi: 10.1007/s00412-010-0286-5. Epub 2010 Jul 24.
PMID 20658144
 
Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta.
Cingolani G, Bednenko J, Gillespie MT, Gerace L.
Mol Cell. 2002 Dec;10(6):1345-53.
PMID 12504010
 
Karyopherin flexibility in nucleocytoplasmic transport.
Conti E, Muller CW, Stewart M.
Curr Opin Struct Biol. 2006 Apr;16(2):237-44. Epub 2006 Mar 29. (REVIEW)
PMID 16567089
 
Importin alpha/beta and Ran-GTP regulate XCTK2 microtubule binding through a bipartite nuclear localization signal.
Ems-McClung SC, Zheng Y, Walczak CE.
Mol Biol Cell. 2004 Jan;15(1):46-57. Epub 2003 Sep 17.
PMID 13679510
 
A novel Crumbs3 isoform regulates cell division and ciliogenesis via importin beta interactions.
Fan S, Fogg V, Wang Q, Chen XW, Liu CJ, Margolis B.
J Cell Biol. 2007 Jul 30;178(3):387-98. Epub 2007 Jul 23.
PMID 17646395
 
Regulation of nucleocytoplasmic trafficking of viral proteins: an integral role in pathogenesis?
Fulcher AJ, Jans DA.
Biochim Biophys Acta. 2011 Dec;1813(12):2176-90. doi: 10.1016/j.bbamcr.2011.03.019. Epub 2011 Apr 16. (REVIEW)
PMID 21530593
 
Transport between the cell nucleus and the cytoplasm.
Gorlich D, Kutay U.
Annu Rev Cell Dev Biol. 1999;15:607-60. (REVIEW)
PMID 10611974
 
Ran induces spindle assembly by reversing the inhibitory effect of importin alpha on TPX2 activity.
Gruss OJ, Carazo-Salas RE, Schatz CA, Guarguaglini G, Kast J, Wilm M, Le Bot N, Vernos I, Karsenti E, Mattaj IW.
Cell. 2001 Jan 12;104(1):83-93.
PMID 11163242
 
Orchestrating nuclear envelope disassembly and reassembly during mitosis.
Guttinger S, Laurell E, Kutay U.
Nat Rev Mol Cell Biol. 2009 Mar;10(3):178-91. doi: 10.1038/nrm2641. (REVIEW)
PMID 19234477
 
Importin beta negatively regulates nuclear membrane fusion and nuclear pore complex assembly.
Harel A, Chan RC, Lachish-Zalait A, Zimmerman E, Elbaum M, Forbes DJ.
Mol Biol Cell. 2003 Nov;14(11):4387-96. Epub 2003 Aug 7.
PMID 14551248
 
Importin beta: conducting a much larger cellular symphony.
Harel A, Forbes DJ.
Mol Cell. 2004 Nov 5;16(3):319-30. (REVIEW)
PMID 15525506
 
Identification of a small molecule inhibitor of importin beta mediated nuclear import by confocal on-bead screening of tagged one-bead one-compound libraries.
Hintersteiner M, Ambrus G, Bednenko J, Schmied M, Knox AJ, Meisner NC, Gstach H, Seifert JM, Singer EL, Gerace L, Auer M.
ACS Chem Biol. 2010 Oct 15;5(10):967-79. doi: 10.1021/cb100094k.
PMID 20677820
 
Importin alpha mRNAs have distinct expression profiles during spermatogenesis.
Hogarth CA, Calanni S, Jans DA, Loveland KL.
Dev Dyn. 2006 Jan;235(1):253-62.
PMID 16261624
 
The RanGAP1-RanBP2 complex is essential for microtubule-kinetochore interactions in vivo.
Joseph J, Liu ST, Jablonski SA, Yen TJ, Dasso M.
Curr Biol. 2004 Apr 6;14(7):611-7.
PMID 15062103
 
SUMO-1 targets RanGAP1 to kinetochores and mitotic spindles.
Joseph J, Tan SH, Karpova TS, McNally JG, Dasso M.
J Cell Biol. 2002 Feb 18;156(4):595-602. Epub 2002 Feb 18.
PMID 11854305
 
The RanGTP gradient - a GPS for the mitotic spindle.
Kalab P, Heald R.
J Cell Sci. 2008 May 15;121(Pt 10):1577-86. doi: 10.1242/jcs.005959.
PMID 18469014
 
Analysis of a RanGTP-regulated gradient in mitotic somatic cells.
Kalab P, Pralle A, Isacoff EY, Heald R, Weis K.
Nature. 2006 Mar 30;440(7084):697-701.
PMID 16572176
 
Importin b1 protein-mediated nuclear localization of death receptor 5 (DR5) limits DR5/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell death of human tumor cells.
Kojima Y, Nakayama M, Nishina T, Nakano H, Koyanagi M, Takeda K, Okumura K, Yagita H.
J Biol Chem. 2011 Dec 16;286(50):43383-93. doi: 10.1074/jbc.M111.309377. Epub 2011 Oct 21.
PMID 22020938
 
The nuclear pore complex becomes alive: new insights into its dynamics and involvement in different cellular processes.
Koser J, Maco B, Aebi U, Fahrenkrog B.
Atlas Genet Cytogenet Oncol Haematol. March 2005. URL: http://AtlasGeneticsOncology.org/Deep/NuclearPoreComplID20048.html
 
Dominant-negative mutants of importin-beta block multiple pathways of import and export through the nuclear pore complex.
Kutay U, Izaurralde E, Bischoff FR, Mattaj IW, Gorlich D.
EMBO J. 1997 Mar 17;16(6):1153-63.
PMID 9135132
 
Global enhancement of nuclear localization-dependent nuclear transport in transformed cells.
Kuusisto HV, Wagstaff KM, Alvisi G, Roth DM, Jans DA.
FASEB J. 2012 Mar;26(3):1181-93. doi: 10.1096/fj.11-191585. Epub 2011 Dec 12.
PMID 22155563
 
Requirement for lamin B receptor and its regulation by importin {beta} and phosphorylation in nuclear envelope assembly during mitotic exit.
Lu X, Shi Y, Lu Q, Ma Y, Luo J, Wang Q, Ji J, Jiang Q, Zhang C.
J Biol Chem. 2010 Oct 22;285(43):33281-93. doi: 10.1074/jbc.M110.102368. Epub 2010 Jun 24.
PMID 20576617
 
Xnf7 contributes to spindle integrity through its microtubule-bundling activity.
Maresca TJ, Niederstrasser H, Weis K, Heald R.
Curr Biol. 2005 Oct 11;15(19):1755-61.
PMID 16213823
 
Molecular basis for specificity of nuclear import and prediction of nuclear localization.
Marfori M, Mynott A, Ellis JJ, Mehdi AM, Saunders NF, Curmi PM, Forwood JK, Boden M, Kobe B.
Biochim Biophys Acta. 2011 Sep;1813(9):1562-77. doi: 10.1016/j.bbamcr.2010.10.013. Epub 2010 Oct 25. (REVIEW)
PMID 20977914
 
Functional genetic screens identify genes essential for tumor cell survival in head and neck and lung cancer.
Martens-de Kemp SR, Nagel R, Stigter-van Walsum M, van der Meulen IH, van Beusechem VW, Braakhuis BJ, Brakenhoff RH.
Clin Cancer Res. 2013 Apr 15;19(8):1994-2003. doi: 10.1158/1078-0432.CCR-12-2539. Epub 2013 Feb 26.
PMID 23444224
 
K-fibre minus ends are stabilized by a RanGTP-dependent mechanism essential for functional spindle assembly.
Meunier S, Vernos I.
Nat Cell Biol. 2011 Nov 13;13(12):1406-14. doi: 10.1038/ncb2372.
PMID 22081094
 
Molecular basis for the recognition of snurportin 1 by importin beta.
Mitrousis G, Olia AS, Walker-Kopp N, Cingolani G.
J Biol Chem. 2008 Mar 21;283(12):7877-84. doi: 10.1074/jbc.M709093200. Epub 2008 Jan 9.
PMID 18187419
 
The two steps of nuclear import, targeting to the nuclear envelope and translocation through the nuclear pore, require different cytosolic factors.
Moore MS, Blobel G.
Cell. 1992 Jun 12;69(6):939-50.
PMID 1606616
 
Nuclear protein import: Ran-GTP dissociates the karyopherin alphabeta heterodimer by displacing alpha from an overlapping binding site on beta.
Moroianu J, Blobel G, Radu A.
Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7059-62.
PMID 8692944
 
Karyopherins: from nuclear-transport mediators to nuclear-function regulators.
Mosammaparast N, Pemberton LF.
Trends Cell Biol. 2004 Oct;14(10):547-56.
PMID 15450977
 
Importin beta is a mitotic target of the small GTPase Ran in spindle assembly.
Nachury MV, Maresca TJ, Salmon WC, Waterman-Storer CM, Heald R, Weis K.
Cell. 2001 Jan 12;104(1):95-106.
PMID 11163243
 
Relative contributions of chromatin and kinetochores to mitotic spindle assembly.
O'Connell CB, Loncarek J, Kalab P, Khodjakov A.
J Cell Biol. 2009 Oct 5;187(1):43-51. doi: 10.1083/jcb.200903076.
PMID 19805628
 
Evolution of the karyopherin-beta family of nucleocytoplasmic transport factors; ancient origins and continued specialization.
O'Reilly AJ, Dacks JB, Field MC.
PLoS One. 2011 Apr 27;6(4):e19308. doi: 10.1371/journal.pone.0019308.
PMID 21556326
 
Molecular interactions between the importin alpha/beta heterodimer and proteins involved in vertebrate nuclear protein import.
Percipalle P, Clarkson WD, Kent HM, Rhodes D, Stewart M.
J Mol Biol. 1997 Mar 7;266(4):722-32.
PMID 9102465
 
Evolutionary and transcriptional analysis of karyopherin beta superfamily proteins.
Quan Y, Ji ZL, Wang X, Tartakoff AM, Tao T.
Mol Cell Proteomics. 2008 Jul;7(7):1254-69. doi: 10.1074/mcp.M700511-MCP200. Epub 2008 Mar 18.
PMID 18353765
 
In vivo analysis of importin alpha proteins reveals cellular proliferation inhibition and substrate specificity.
Quensel C, Friedrich B, Sommer T, Hartmann E, Kohler M.
Mol Cell Biol. 2004 Dec;24(23):10246-55.
PMID 15542834
 
Identification of a protein complex that is required for nuclear protein import and mediates docking of import substrate to distinct nucleoporins.
Radu A, Blobel G, Moore MS.
Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1769-73.
PMID 7878057
 
RAN (RAN, member RAS oncogene family).
Rensen WM, Lavia P.
Atlas Genet Cytogenet Oncol Haematol. November 2009. URL: http://AtlasGeneticsOncology.org/Genes/RANID4203912q24.html
 
The GTPase Ran: regulation of cell life and potential roles in cell transformation.
Rensen WM, Mangiacasale R, Ciciarello M, Lavia P.
Front Biosci. 2008 May 1;13:4097-121. (REVIEW)
PMID 18508502
 
NuSAP, a mitotic RanGTP target that stabilizes and cross-links microtubules.
Ribbeck K, Groen AC, Santarella R, Bohnsack MT, Raemaekers T, Kocher T, Gentzel M, Gorlich D, Wilm M, Carmeliet G, Mitchison TJ, Ellenberg J, Hoenger A, Mattaj IW.
Mol Biol Cell. 2006 Jun;17(6):2646-60. Epub 2006 Mar 29.
PMID 16571672
 
The adapter importin-alpha provides flexible control of nuclear import at the expense of efficiency.
Riddick G, Macara IG.
Mol Syst Biol. 2007;3:118. Epub 2007 Jun 5.
PMID 17551513
 
Importin-beta negatively regulates multiple aspects of mitosis including RANGAP1 recruitment to kinetochores.
Roscioli E, Di Francesco L, Bolognesi A, Giubettini M, Orlando S, Harel A, Schinina ME, Lavia P.
J Cell Biol. 2012 Feb 20;196(4):435-50. doi: 10.1083/jcb.201109104. Epub 2012 Feb 13.
PMID 22331847
 
Importin beta regulates the seeding of chromatin with initiation sites for nuclear pore assembly.
Rotem A, Gruber R, Shorer H, Shaulov L, Klein E, Harel A.
Mol Biol Cell. 2009 Sep;20(18):4031-42. doi: 10.1091/mbc.E09-02-0150. Epub 2009 Jul 22.
PMID 19625448
 
XPO1 (exportin 1 (CRM1 homolog, yeast))
Ruggiero A, Giubettini M, Lavia P.
Atlas Genet Cytogenet Oncol Haematol. November 2011. URL: http://AtlasGeneticsOncology.org/Genes/XPO1ID44168ch2p15.html
 
Structural and biochemical characterization of the Importin-beta.Ran.GTP.RanBD1 complex.
Saric' M, Zhao X, Korner C, Nowak C, Kuhlmann J, Vetter IR.
FEBS Lett. 2007 Apr 3;581(7):1369-76. Epub 2007 Mar 6.
PMID 17359978
 
Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells.
Schmitz MH, Held M, Janssens V, Hutchins JR, Hudecz O, Ivanova E, Goris J, Trinkle-Mulcahy L, Lamond AI, Poser I, Hyman AA, Mechtler K, Peters JM, Gerlich DW.
Nat Cell Biol. 2010 Sep;12(9):886-93. doi: 10.1038/ncb2092. Epub 2010 Aug 15.
PMID 20711181
 
HURP is a Ran-importin beta-regulated protein that stabilizes kinetochore microtubules in the vicinity of chromosomes.
Sillje HH, Nagel S, Korner R, Nigg EA.
Curr Biol. 2006 Apr 18;16(8):731-42.
PMID 16631580
 
Nuclear entry of activated MAPK is restricted in primary ovarian and mammary epithelial cells.
Smith ER, Cai KQ, Smedberg JL, Ribeiro MM, Rula ME, Slater C, Godwin AK, Xu XX.
PLoS One. 2010 Feb 18;5(2):e9295. doi: 10.1371/journal.pone.0009295.
PMID 20174585
 
Importazole, a small molecule inhibitor of the transport receptor importin-beta.
Soderholm JF, Bird SL, Kalab P, Sampathkumar Y, Hasegawa K, Uehara-Bingen M, Weis K, Heald R.
ACS Chem Biol. 2011 Jul 15;6(7):700-8. doi: 10.1021/cb2000296. Epub 2011 Apr 21.
PMID 21469738
 
Regulated degradation of spindle assembly factors by the anaphase-promoting complex.
Song L, Rape M.
Mol Cell. 2010 May 14;38(3):369-82. doi: 10.1016/j.molcel.2010.02.038.
PMID 20471943
 
Importin-beta-like nuclear transport receptors.
Strom AC, Weis K.
Genome Biol. 2001;2(6):REVIEWS3008. Epub 2001 Jun 5. (REVIEW)
PMID 11423015
 
Importin-beta and the small guanosine triphosphatase Ran mediate chromosome loading of the human chromokinesin Kid.
Tahara K, Takagi M, Ohsugi M, Sone T, Nishiumi F, Maeshima K, Horiuchi Y, Tokai-Nishizumi N, Imamoto F, Yamamoto T, Kose S, Imamoto N.
J Cell Biol. 2008 Feb 11;180(3):493-506. doi: 10.1083/jcb.200708003.
PMID 18268099
 
Localized RanGTP accumulation promotes microtubule nucleation at kinetochores in somatic mammalian cells.
Torosantucci L, De Luca M, Guarguaglini G, Lavia P, Degrassi F.
Mol Biol Cell. 2008 May;19(5):1873-82. doi: 10.1091/mbc.E07-10-1050. Epub 2008 Feb 20.
PMID 18287525
 
Ran modulates spindle assembly by regulating a subset of TPX2 and Kid activities including Aurora A activation.
Trieselmann N, Armstrong S, Rauw J, Wilde A.
J Cell Sci. 2003 Dec 1;116(Pt 23):4791-8.
PMID 14600264
 
Molecular requirements for kinetochore-associated microtubule formation in mammalian cells.
Tulu US, Fagerstrom C, Ferenz NP, Wadsworth P.
Curr Biol. 2006 Mar 7;16(5):536-41.
PMID 16527751
 
Repo-Man coordinates chromosomal reorganization with nuclear envelope reassembly during mitotic exit.
Vagnarelli P, Ribeiro S, Sennels L, Sanchez-Pulido L, de Lima Alves F, Verheyen T, Kelly DA, Ponting CP, Rappsilber J, Earnshaw WC.
Dev Cell. 2011 Aug 16;21(2):328-42. doi: 10.1016/j.devcel.2011.06.020. Epub 2011 Aug 4.
PMID 21820363
 
Structure of a Ran-binding domain complexed with Ran bound to a GTP analogue: implications for nuclear transport.
Vetter IR, Nowak C, Nishimoto T, Kuhlmann J, Wittinghofer A.
Nature. 1999 Mar 4;398(6722):39-46.
PMID 10078529
 
smoothened and thickveins regulate Moleskin/Importin 7-mediated MAP kinase signaling in the developing Drosophila eye.
Vrailas AD, Marenda DR, Cook SE, Powers MA, Lorenzen JA, Perkins LA, Moses K.
Development. 2006 Apr;133(8):1485-94. Epub 2006 Mar 15.
PMID 16540506
 
Role of importin-beta in coupling Ran to downstream targets in microtubule assembly.
Wiese C, Wilde A, Moore MS, Adam SA, Merdes A, Zheng Y.
Science. 2001 Jan 26;291(5504):653-6.
PMID 11229403
 
A novel karyopherin-beta homolog is developmentally and hormonally regulated in fetal lung.
Zhang C, Sweezey NB, Gagnon S, Muskat B, Koehler D, Post M, Kaplan F.
Am J Respir Cell Mol Biol. 2000 Apr;22(4):451-9.
PMID 10745026
 
The nuclear import receptor Kpnb1 and its potential as an anticancer therapeutic target.
van der Watt PJ, Stowell CL, Leaner VD.
Crit Rev Eukaryot Gene Expr. 2013;23(1):1-10.
PMID 23557333
 

Citation

This paper should be referenced as such :
Giubettini, M ; van, der Watt P ; Verrico, A ; de, Turris V ; Leaner, V ; Lavia, P
KPNB1 (karyopherin (importin) beta 1)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(10):689-698.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/KPNB1ID41101ch17q21.html


External links

Nomenclature
HGNC (Hugo)KPNB1   6400
Cards
AtlasKPNB1ID41101ch17q21
Entrez_Gene (NCBI)KPNB1  3837  karyopherin subunit beta 1
AliasesIMB1; IPO1; IPOB; Impnb; 
NTF97
GeneCards (Weizmann)KPNB1
Ensembl hg19 (Hinxton)ENSG00000108424 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000108424 [Gene_View]  chr17:47651196-47683638 [Contig_View]  KPNB1 [Vega]
ICGC DataPortalENSG00000108424
TCGA cBioPortalKPNB1
AceView (NCBI)KPNB1
Genatlas (Paris)KPNB1
WikiGenes3837
SOURCE (Princeton)KPNB1
Genetics Home Reference (NIH)KPNB1
Genomic and cartography
GoldenPath hg38 (UCSC)KPNB1  -     chr17:47651196-47683638 +  17q21.32   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)KPNB1  -     17q21.32   [Description]    (hg19-Feb_2009)
EnsemblKPNB1 - 17q21.32 [CytoView hg19]  KPNB1 - 17q21.32 [CytoView hg38]
Mapping of homologs : NCBIKPNB1 [Mapview hg19]  KPNB1 [Mapview hg38]
OMIM602738   
Gene and transcription
Genbank (Entrez)AI076614 AK299145 AK301463 AK314780 AK316421
RefSeq transcript (Entrez)NM_001276453 NM_002265
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)KPNB1
Cluster EST : UnigeneHs.532793 [ NCBI ]
CGAP (NCI)Hs.532793
Alternative Splicing GalleryENSG00000108424
Gene ExpressionKPNB1 [ NCBI-GEO ]   KPNB1 [ EBI - ARRAY_EXPRESS ]   KPNB1 [ SEEK ]   KPNB1 [ MEM ]
Gene Expression Viewer (FireBrowse)KPNB1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3837
GTEX Portal (Tissue expression)KPNB1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ14974   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ14974  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ14974
Splice isoforms : SwissVarQ14974
PhosPhoSitePlusQ14974
Domaine pattern : Prosite (Expaxy)HEAT_REPEAT (PS50077)    IMPORTIN_B_NT (PS50166)   
Domains : Interpro (EBI)ARM-like    ARM-type_fold    Armadillo    HEAT_type_2    Importin-beta_N   
Domain families : Pfam (Sanger)IBN_N (PF03810)   
Domain families : Pfam (NCBI)pfam03810   
Domain families : Smart (EMBL)ARM (SM00185)  IBN_N (SM00913)  
Conserved Domain (NCBI)KPNB1
DMDM Disease mutations3837
Blocks (Seattle)KPNB1
PDB (SRS)1F59    1IBR    1M5N    1O6O    1O6P    1QGK    1QGR    2P8Q    2Q5D    2QNA    3LWW    3W5K   
PDB (PDBSum)1F59    1IBR    1M5N    1O6O    1O6P    1QGK    1QGR    2P8Q    2Q5D    2QNA    3LWW    3W5K   
PDB (IMB)1F59    1IBR    1M5N    1O6O    1O6P    1QGK    1QGR    2P8Q    2Q5D    2QNA    3LWW    3W5K   
PDB (RSDB)1F59    1IBR    1M5N    1O6O    1O6P    1QGK    1QGR    2P8Q    2Q5D    2QNA    3LWW    3W5K   
Structural Biology KnowledgeBase1F59    1IBR    1M5N    1O6O    1O6P    1QGK    1QGR    2P8Q    2Q5D    2QNA    3LWW    3W5K   
SCOP (Structural Classification of Proteins)1F59    1IBR    1M5N    1O6O    1O6P    1QGK    1QGR    2P8Q    2Q5D    2QNA    3LWW    3W5K   
CATH (Classification of proteins structures)1F59    1IBR    1M5N    1O6O    1O6P    1QGK    1QGR    2P8Q    2Q5D    2QNA    3LWW    3W5K   
SuperfamilyQ14974
Human Protein AtlasENSG00000108424
Peptide AtlasQ14974
HPRD04114
IPIIPI00001639   IPI01010020   IPI00922792   
Protein Interaction databases
DIP (DOE-UCLA)Q14974
IntAct (EBI)Q14974
FunCoupENSG00000108424
BioGRIDKPNB1
STRING (EMBL)KPNB1
ZODIACKPNB1
Ontologies - Pathways
QuickGOQ14974
Ontology : AmiGOprotein import into nucleus, translocation  RNA binding  protein binding  extracellular region  nuclear envelope  nuclear pore  nucleoplasm  nucleoplasm  cytoplasm  cytosol  cytosol  apoptotic DNA fragmentation  protein import into nucleus  NLS-bearing protein import into nucleus  ribosomal protein import into nucleus  mitotic chromosome movement towards spindle pole  mitotic metaphase plate congression  nuclear localization sequence binding  zinc ion binding  Ran GTPase binding  protein transporter activity  membrane  modulation by virus of host process  enzyme binding  protein domain specific binding  astral microtubule organization  Ran protein signal transduction  nuclear membrane  nuclear membrane  nuclear periphery  specific granule lumen  establishment of mitotic spindle localization  neutrophil degranulation  establishment of protein localization  Hsp90 protein binding  extracellular exosome  endoplasmic reticulum tubular network  intracellular transport of virus  mitotic spindle assembly  ficolin-1-rich granule lumen  
Ontology : EGO-EBIprotein import into nucleus, translocation  RNA binding  protein binding  extracellular region  nuclear envelope  nuclear pore  nucleoplasm  nucleoplasm  cytoplasm  cytosol  cytosol  apoptotic DNA fragmentation  protein import into nucleus  NLS-bearing protein import into nucleus  ribosomal protein import into nucleus  mitotic chromosome movement towards spindle pole  mitotic metaphase plate congression  nuclear localization sequence binding  zinc ion binding  Ran GTPase binding  protein transporter activity  membrane  modulation by virus of host process  enzyme binding  protein domain specific binding  astral microtubule organization  Ran protein signal transduction  nuclear membrane  nuclear membrane  nuclear periphery  specific granule lumen  establishment of mitotic spindle localization  neutrophil degranulation  establishment of protein localization  Hsp90 protein binding  extracellular exosome  endoplasmic reticulum tubular network  intracellular transport of virus  mitotic spindle assembly  ficolin-1-rich granule lumen  
Pathways : BIOCARTARole of Ran in mitotic spindle regulation [Genes]    Mechanism of Protein Import into the Nucleus [Genes]   
Pathways : KEGGRNA transport   
REACTOMEQ14974 [protein]
REACTOME PathwaysR-HSA-6798695 [pathway]   
NDEx NetworkKPNB1
Atlas of Cancer Signalling NetworkKPNB1
Wikipedia pathwaysKPNB1
Orthology - Evolution
OrthoDB3837
GeneTree (enSembl)ENSG00000108424
Phylogenetic Trees/Animal Genes : TreeFamKPNB1
HOVERGENQ14974
HOGENOMQ14974
Homologs : HomoloGeneKPNB1
Homology/Alignments : Family Browser (UCSC)KPNB1
Gene fusions - Rearrangements
Fusion : MitelmanKPNB1/ACE [17q21.32/17q23.3]  
Fusion : MitelmanKPNB1/SKAP1 [17q21.32/17q21.32]  [t(17;17)(q21;q21)]  
Fusion: TCGAKPNB1 17q21.32 SKAP1 17q21.32 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKPNB1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KPNB1
dbVarKPNB1
ClinVarKPNB1
1000_GenomesKPNB1 
Exome Variant ServerKPNB1
ExAC (Exome Aggregation Consortium)KPNB1 (select the gene name)
Genetic variants : HAPMAP3837
Genomic Variants (DGV)KPNB1 [DGVbeta]
DECIPHERKPNB1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisKPNB1 
Mutations
ICGC Data PortalKPNB1 
TCGA Data PortalKPNB1 
Broad Tumor PortalKPNB1
OASIS PortalKPNB1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICKPNB1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDKPNB1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch KPNB1
DgiDB (Drug Gene Interaction Database)KPNB1
DoCM (Curated mutations)KPNB1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KPNB1 (select a term)
intoGenKPNB1
NCG5 (London)KPNB1
Cancer3DKPNB1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM602738   
Orphanet
MedgenKPNB1
Genetic Testing Registry KPNB1
NextProtQ14974 [Medical]
TSGene3837
GENETestsKPNB1
Target ValidationKPNB1
Huge Navigator KPNB1 [HugePedia]
snp3D : Map Gene to Disease3837
BioCentury BCIQKPNB1
ClinGenKPNB1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3837
Chemical/Pharm GKB GenePA30191
Clinical trialKPNB1
Miscellaneous
canSAR (ICR)KPNB1 (select the gene name)
Probes
Litterature
PubMed296 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineKPNB1
EVEXKPNB1
GoPubMedKPNB1
iHOPKPNB1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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