Opinion
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.
Acknowledgment
Our work is supported by the CNR Flagship “InterOmics” project.
Bibliography
  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.

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