Volume 1 Issue 1 - 2016
Nuclear Transport Receptors: Moonlighting Proteins Aberrantly Expressed in Cancer
Annalisa Verrico1*, Maria Eugenia Schininà2, Laura Di Francesco2, Andrea Ilari1, Veronica Morea1 and Patrizia Lavia1
1Institute of Molecular Biology and Pathology, CNR Consiglio Nazionale delle Ricerche, Rome, Italy
2Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
*Corresponding Author: Annalisa Verrico, Institute of Molecular Biology and Pathology, CNR Consiglio Nazionale delle Ricerche, Rome, Italy.
Received: July 29, 2016; Published: August 23, 2016
Citation: Annalisa Verrico. “Nuclear Transport Receptors: Moonlighting Proteins Aberrantly Expressed in Cancer”. EC Proteomics and Bioinformatics 1.1 (2016): 01-03.
The concept of moonlighting proteins has emerged in the last years to indicate proteins that serve more than one function, and/or act in independent processes. Moonlighting proteins are examples of “functional re-adaptation” to the changing needs of different cell types, context, biological or environmental conditions. These proteins are being demonstrated to be of growing importance in biological processes and dedicated databases are being constructed [1-3].
Some members of the karyopherin family of nuclear transport receptors (i.e., importin beta-1, alpha-1, alpha-3, beta-2/transport in, import in 13, and export in-1/XPO1/CRM1) are recognized in at least one of the moonlighting databases for having a double role. We previously illustrated the moonlighting functions of human importin beta-1 by proteomic detection of its mitotic interactors, coupled with time-lapse imaging of mitotic cells that overexpress it: we reported that importin beta-1 regulates the timing of kinetochore delivery of two proteins whose pathways are important for kinetochore function during mitosis: the RAN GTPase regulator RANGAP1, and the SUMO ligase RANBP2 [4].
Interactomic studies ongoing in our laboratory are expanding the list of both “constitutive” and cell cycle phase-specific, alternative molecular cargos that importin beta-1 is able to interact with during cell cycle progression. These findings indicate that importin beta-1’s moonlighting functions are even more intricate than previously thought. In-depth analyses of the three-dimensional structures of importin beta-1 available from the Protein Data Bank [5] provided us with rational bases to build models for importin beta-1 interactions with specific mitotic targets and to predict how importin beta-1 deregulated levels might affect the function of those targets during mitosis.
We propose that all nuclear transport receptors are bonafide moonlighting proteins with distinct functions in distinct cell cycle stages or cell types. In interphase they interact with proteins tagged by nuclear localization signals (NLS) or nuclear export signals (NES), and transport them in and out of the nucleus to operate in their physiological subcellular compartments. In mitosis, when nucleo-cytoplasmic transport ceases, they are functionally “recycled” to orchestrate new functions at mitotic structures: centrosomes, asters, mitotic spindle poles, microtubules and chromosomal kinetochores [6,7] (importin beta-1 is depicted in Fig. 1). Some karyopherin family members act in specialized communication in neurons [8] and/or at a centrosome-related organelle, the cilium, present in some cell types including neuronal subtypes [9,10]. Remarkably, the pathological consequences of nuclear transport receptor dysfunction, i.e. abnormal mitosis originating genetic instability - a cancer hallmark - and complex syndromes such as ciliopathies, are attributable to their “secondary” functions.
rowing evidence indicate that nuclear transport receptors are abnormally expressed in cancer types [11,12]. Efforts are being made to develop inhibitors with potentially therapeutic purposes [13,18]. Implementation of ad hoc bioinformatics and proteomic studies is essential to reveal the full extent of promiscuity and moonlighting functions of nuclear transport receptors and identify molecular features involved in specific interactions. This, in turn, is the required basis to rationally design compounds potentially effective in cancer contexts in which these receptors are aberrantly expressed.
Figure 1: The localization of importin beta-1 in human cells illustrates its moonlighting functions during the cell cycle. Top row: importin beta-1 (in red) accumulates at the nuclear envelope encircling the nucleus (blue) in interphase to perform its function as a nuclear transport receptor. Staining of alpha-tubulin (in green) depicts the interphase cytoskeleton. Bottom row: in mitosis importin beta-1 (red) associates with the spindle microtubules (green), with enrichment at the spindle poles, to regulate the activity of the mitotic apparatus and hence segregation of chromosomes (in blue). Regions in which importin-beta 1 overlaps with alpha-tubulin appear in yellow in the merged pictures.
Our work is supported by the CNR Flagship “InterOmics” project.
  1. Hernandez S., et al. “Multitask ProtDB: a database of multitasking proteins”. Nucleic Acids Research 42 (2014): D517-D520.
  2. Chapple CE.,et al. “Extreme multifunctional proteins identified from a human protein interaction network”. Nature Communications 6 (2015): 7412.
  3. Mani M., et al. “MoonProt: a database for proteins that are known to moonlight”. Nucleic Acids Research 43 (2015): D277-D282.
  4. Roscioli E., et al. “Importin-β negatively regulates multiple aspects of mitosis including RANGAP1 recruitment to kinetochores”. Journal of Cell Biology 196 (2012): 435-450.
  5. Berman H., et al. “The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data”. Nucleic Acids Research: Oxford Journals 35.1 (2007): D301-D303.
  6. Forbes DJ., et al. “Nuclear transport factors: global regulation of mitosis”. Current Opinion in Cell Biology 35 (2015): 78-90.
  7. Cavazza T and Vernos I. (2016). “The RanGTP Pathway: From Nucleo-Cytoplasmic Transport to Spindle Assembly and Beyond”. Frontiers in Cell and Developmental Biology 3 (2016): 82.
  8. Rishal I and Fainzilber M. “Axon-soma communication in neuronal injury”. Nature Reviews Neuroscience 15 (2014): 32-42.
  9. Gruss OJ. “Nuclear transport receptor goes moonlighting”. Nature Cell Biology 12 (2010): 640-641.
  10. Takao D and Verhey KJ. “Gated entry into the ciliary compartment”. Cellular and Molecular Life Sciences 73.1 (2016): 119-127.
  11. van der Watt PJ., et al. “The Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation”. International Journal of Cancer 124.8 (2009): 1829-1840.
  12. van der Watt PJ., et al. “Elevated expression of the nuclear export protein, Crm1 (exportin 1), associates with human oesophageal squamous cell carcinoma”. Oncology Reports 32.2 (2014): 730-738.
  13. Soderholm JF., et al. “Importazole, a small molecule inhibitor of the transport receptor importin-β”. ACS Chemical Biology 6 (2011): 700-708.
  14. van der Watt PJ., et al. “The nuclear import receptor Kpnβ1 and its potential as an anticancer therapeutic target”. Critical Reviews™ in Eukaryotic Gene Expression 23.1 (2013): 1-10.
  15. Gravina GL., et al. “Nucleo-cytoplasmic transport as a therapeutic target of cancer”. Journal of Hematology & Oncology 7 (2014): 85.
  16. van der Watt PJ., et al. “Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic”. Molecular Cancer Therapeutics 15.4 (2016): 560-573.
  17. Stelma T., et al. “Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential”. IUBMB Life 68 (2016): 268-280.
  18. Mahipal A and Malafa M. “Importins and exportins as therapeutic targets in cancer”. Pharmacology & Therapeutics 164 (2016): 135-143.
Copyright: © 2016 Annalisa Verrico. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PubMed Indexed Article

EC Pharmacology and Toxicology
LC-UV-MS and MS/MS Characterize Glutathione Reactivity with Different Isomers (2,2' and 2,4' vs. 4,4') of Methylene Diphenyl-Diisocyanate.

PMID: 31143884 [PubMed]

PMCID: PMC6536005

EC Pharmacology and Toxicology
Alzheimer's Pathogenesis, Metal-Mediated Redox Stress, and Potential Nanotheranostics.

PMID: 31565701 [PubMed]

PMCID: PMC6764777

EC Neurology
Differences in Rate of Cognitive Decline and Caregiver Burden between Alzheimer's Disease and Vascular Dementia: a Retrospective Study.

PMID: 27747317 [PubMed]

PMCID: PMC5065347

EC Pharmacology and Toxicology
Will Blockchain Technology Transform Healthcare and Biomedical Sciences?

PMID: 31460519 [PubMed]

PMCID: PMC6711478

EC Pharmacology and Toxicology
Is it a Prime Time for AI-powered Virtual Drug Screening?

PMID: 30215059 [PubMed]

PMCID: PMC6133253

EC Psychology and Psychiatry
Analysis of Evidence for the Combination of Pro-dopamine Regulator (KB220PAM) and Naltrexone to Prevent Opioid Use Disorder Relapse.

PMID: 30417173 [PubMed]

PMCID: PMC6226033

EC Anaesthesia
Arrest Under Anesthesia - What was the Culprit? A Case Report.

PMID: 30264037 [PubMed]

PMCID: PMC6155992

EC Orthopaedics
Distraction Implantation. A New Technique in Total Joint Arthroplasty and Direct Skeletal Attachment.

PMID: 30198026 [PubMed]

PMCID: PMC6124505

EC Pulmonology and Respiratory Medicine
Prevalence and factors associated with self-reported chronic obstructive pulmonary disease among adults aged 40-79: the National Health and Nutrition Examination Survey (NHANES) 2007-2012.

PMID: 30294723 [PubMed]

PMCID: PMC6169793

EC Dental Science
Important Dental Fiber-Reinforced Composite Molding Compound Breakthroughs

PMID: 29285526 [PubMed]

PMCID: PMC5743211

EC Microbiology
Prevalence of Intestinal Parasites Among HIV Infected and HIV Uninfected Patients Treated at the 1o De Maio Health Centre in Maputo, Mozambique

PMID: 29911204 [PubMed]

PMCID: PMC5999047

EC Microbiology
Macrophages and the Viral Dissemination Super Highway

PMID: 26949751 [PubMed]

PMCID: PMC4774560

EC Microbiology
The Microbiome, Antibiotics, and Health of the Pediatric Population.

PMID: 27390782 [PubMed]

PMCID: PMC4933318

EC Microbiology
Reactive Oxygen Species in HIV Infection

PMID: 28580453 [PubMed]

PMCID: PMC5450819

EC Microbiology
A Review of the CD4 T Cell Contribution to Lung Infection, Inflammation and Repair with a Focus on Wheeze and Asthma in the Pediatric Population

PMID: 26280024 [PubMed]

PMCID: PMC4533840

EC Neurology
Identifying Key Symptoms Differentiating Myalgic Encephalomyelitis and Chronic Fatigue Syndrome from Multiple Sclerosis

PMID: 28066845 [PubMed]

PMCID: PMC5214344

EC Pharmacology and Toxicology
Paradigm Shift is the Normal State of Pharmacology

PMID: 28936490 [PubMed]

PMCID: PMC5604476

EC Neurology
Examining those Meeting IOM Criteria Versus IOM Plus Fibromyalgia

PMID: 28713879 [PubMed]

PMCID: PMC5510658

EC Neurology
Unilateral Frontosphenoid Craniosynostosis: Case Report and a Review of the Literature

PMID: 28133641 [PubMed]

PMCID: PMC5267489

EC Ophthalmology
OCT-Angiography for Non-Invasive Monitoring of Neuronal and Vascular Structure in Mouse Retina: Implication for Characterization of Retinal Neurovascular Coupling

PMID: 29333536 [PubMed]

PMCID: PMC5766278

EC Neurology
Longer Duration of Downslope Treadmill Walking Induces Depression of H-Reflexes Measured during Standing and Walking.

PMID: 31032493 [PubMed]

PMCID: PMC6483108

EC Microbiology
Onchocerciasis in Mozambique: An Unknown Condition for Health Professionals.

PMID: 30957099 [PubMed]

PMCID: PMC6448571

EC Nutrition
Food Insecurity among Households with and without Podoconiosis in East and West Gojjam, Ethiopia.

PMID: 30101228 [PubMed]

PMCID: PMC6086333

EC Ophthalmology
REVIEW. +2 to +3 D. Reading Glasses to Prevent Myopia.

PMID: 31080964 [PubMed]

PMCID: PMC6508883

EC Gynaecology
Biomechanical Mapping of the Female Pelvic Floor: Uterine Prolapse Versus Normal Conditions.

PMID: 31093608 [PubMed]

PMCID: PMC6513001

EC Dental Science
Fiber-Reinforced Composites: A Breakthrough in Practical Clinical Applications with Advanced Wear Resistance for Dental Materials.

PMID: 31552397 [PubMed]

PMCID: PMC6758937

EC Microbiology
Neurocysticercosis in Child Bearing Women: An Overlooked Condition in Mozambique and a Potentially Missed Diagnosis in Women Presenting with Eclampsia.

PMID: 31681909 [PubMed]

PMCID: PMC6824723

EC Microbiology
Molecular Detection of Leptospira spp. in Rodents Trapped in the Mozambique Island City, Nampula Province, Mozambique.

PMID: 31681910 [PubMed]

PMCID: PMC6824726

EC Neurology
Endoplasmic Reticulum-Mitochondrial Cross-Talk in Neurodegenerative and Eye Diseases.

PMID: 31528859 [PubMed]

PMCID: PMC6746603

EC Psychology and Psychiatry
Can Chronic Consumption of Caffeine by Increasing D2/D3 Receptors Offer Benefit to Carriers of the DRD2 A1 Allele in Cocaine Abuse?

PMID: 31276119 [PubMed]

PMCID: PMC6604646

EC Anaesthesia
Real Time Locating Systems and sustainability of Perioperative Efficiency of Anesthesiologists.

PMID: 31406965 [PubMed]

PMCID: PMC6690616

EC Pharmacology and Toxicology
A Pilot STEM Curriculum Designed to Teach High School Students Concepts in Biochemical Engineering and Pharmacology.

PMID: 31517314 [PubMed]

PMCID: PMC6741290

EC Pharmacology and Toxicology
Toxic Mechanisms Underlying Motor Activity Changes Induced by a Mixture of Lead, Arsenic and Manganese.

PMID: 31633124 [PubMed]

PMCID: PMC6800226

EC Neurology
Research Volunteers' Attitudes Toward Chronic Fatigue Syndrome and Myalgic Encephalomyelitis.

PMID: 29662969 [PubMed]

PMCID: PMC5898812

EC Pharmacology and Toxicology
Hyperbaric Oxygen Therapy for Alzheimer's Disease.

PMID: 30215058 [PubMed]

PMCID: PMC6133268

News and Events

November Issue Release

We always feel pleasure to share our updates with you all. Here, notifying you that we have successfully released the November issue of respective journals and the latest articles can be viewed on the current issue pages.

Submission Deadline for Upcoming Issue

ECronicon delightfully welcomes all the authors around the globe for effective collaboration with an article submission for the upcoming issue of respective journals. Submissions are accepted on/before December 09, 2022.

Certificate of Publication

ECronicon honors with a "Publication Certificate" to the corresponding author by including the names of co-authors as a token of appreciation for publishing the work with our respective journals.

Best Article of the Issue

Editors of respective journals will always be very much interested in electing one Best Article after each issue release. The authors of the selected article will be honored with a "Best Article of the Issue" certificate.

Certifying for Review

ECronicon certifies the Editors for their first review done towards the assigned article of the respective journals.

Latest Articles

The latest articles will be updated immediately on the articles in press page of the respective journals.