ReviewNuclear pore proteins and cancer
Section snippets
The nuclear pore complex
The nuclear pore complex (NPC) is a massive, multiprotein structure responsible for traffic between the nucleus and cytoplasm. The general structure of the NPC is becoming fairly well defined, but the mechanism of translocation through the pore remains incompletely understood. The NPC is comprised of a central core region consisting of nucleoplasmic and cytoplasmic rings joined by a spoke structure (Fig. 1). These are anchored in the nuclear membrane through three transmembrane proteins.
Nup88 in multiple subcomplexes of the NPC
Nup88 is a non-FG nucleoporin found exclusively on the cytoplasmic face of the NPC (Fig. 1). This nucleoporin is comprised of two of the repeating structural motifs of the pore; the N-terminal domain is predicted to form a β-propeller structure and the C-terminal domain contains predicted coiled-coils (Fig. 2A). Nup88 is found in a biochemically defined subcomplex of the pore together with the FG repeat nucleoporin Nup214 [6], [7] and, in some systems, Nup62 [8]. Formation of this complex is
Tpr structure and normal function
Tpr is a 265 kDa nucleoporin found exclusively at the nucleoplasmic face of the pore where it is a major component of the nuclear basket (Fig. 1) [28]. Tpr does not possess nucleoporin FG repeats but it does contain numerous heptad repeat or leucine zipper motifs (Fig. 2B). Tpr is comprised of two domains, a large, approximately 190 kDa N-terminal domain which contains the heptad repeats and an unstructured, acidic C-terminal domain [29]. The heptad repeat region is predicted to form a
Nup98 structure, variants and binding partners
The FG-repeat nucleoporin Nup98 is the only vertebrate nucleoporin with substantial numbers of GLFG-type repeats [48], [49]. Nup98 is expressed in two major forms that vary as a result of differential splicing. The first splice variant encodes a 920 amino acid protein (Fig. 2C); the N-terminal half contains FG and GLFG repeat motifs and is bisected by a small coiled-coil domain (AA 181–224) that binds to the β-propeller nucleoporin Rae1/Gle2 (hereafter referred to as Rae1) [50]. Rae1 is
Nup214 structure and function in the NPC
Nup214 is an FG repeat nucleoporin normally confined to the cytoplasmic face of the NPC (Fig. 1). Nup214 contains repeats of both the FG and FxFG type and its repeat domain is a high affinity binding site for the nuclear protein export receptor, CRM-1/exportin-1. The N-terminus of Nup214 is predicted to form a β-propeller structure, as has been demonstrated for the yeast ortholog, Nup159 [90]. This is followed by a region rich in proline and serine (17% and 25%, respectively), two stretches of
Conclusions
The study of nucleoporins and their roles in cancer has been a fruitful one, revealing novel mechanisms by which cells are advanced along the path to transformation. From our current level of understanding, each nucleoporin contributing to in carcinogenesis seems to do so in a unique manner. It is somewhat surprising that, in the case of nucleoporin translocations, defects in nuclear transport have not been reported. Patient cells are heterozygous for these translocations and thus the level of
Acknowledgements
The authors regret the many publications we were unable to cite due to lack of space. We thank the members of the Powers laboratory, especially Marie Cross and Dr. Amy Pierce for their very helpful discussions and comments on the manuscript, and Dr. Katharine Ullman and Dr. Paula Vertino for comments on the manuscript. Work in the authors’ laboratory is supported by National Institutes of Health grant GM-059975 to M.A.P.
References (151)
- et al.
Dynamic nuclear pore complexes: life on the edge
Cell
(2006) - et al.
Structure, dynamics and function of nuclear pore complexes
Trends Cell Biol
(2008) Modularity within the architecture of the nuclear pore complex
Curr Opin Struct Biol
(2005)- et al.
Differential mitotic phosphorylation of proteins of the nuclear pore complex
J Biol Chem
(1995) - et al.
Nup214-Nup88 nucleoporin subcomplex is required for CRM1-mediated 60 S preribosomal nuclear export
J Biol Chem
(2006) - et al.
Dynamic properties of nuclear pore complex proteins in gp210 deficient cells
FEBS Lett
(2004) - et al.
Limited expression of nuclear pore membrane glycoprotein 210 in cell lines and tissues suggests cell-type specific nuclear pores in metazoans
Exp Cell Res
(2004) - et al.
cDNA cloning and characterization of Npap60: a novel rat nuclear pore-associated protein with an unusual subcellular localization during male germ cell differentiation
Genomics
(1997) - et al.
Nup88 (karyoporin) in human malignant neoplasms and dysplasias: correlations of immunostaining of tissue sections, cytologic smears, and immunoblot analysis
Hum Pathol
(2002) - et al.
A novel, nuclear pore-associated, widely distributed molecule overexpressed in oncogenesis and development
Am J Pathol
(2000)