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Nuclear transport of Ras-associated tumor suppressor proteins: different transport receptor binding specificities for arginine-rich nuclear targeting signals.
- Source :
-
Journal of molecular biology [J Mol Biol] 2007 Apr 13; Vol. 367 (5), pp. 1294-311. Date of Electronic Publication: 2007 Jan 12. - Publication Year :
- 2007
-
Abstract
- Ras proteins regulate a wide range of biological processes by interacting with a variety of effector proteins. In addition to the known role in tumorigensis, the activated form of Ras exhibits growth-inhibitory effects by unknown mechanisms. Several Ras effector proteins identified as mediators of apoptosis and cell-cycle arrest also exhibit properties normally associated with tumor suppressor proteins. Here, we show that Ras effector RASSF5/NORE-1 binds strongly to K-Ras but weakly to both N-Ras and H-Ras. RASSF5 was found to localize both in the nucleus and the nucleolus in contrast to other Ras effector proteins, RASSF1C and RASSF2, which are localized in the nucleus and excluded from nucleolus. A 50 amino acid residue transferable arginine-rich nucleolar localization signal (NoLS) identified in RASSF5 is capable of interacting with importin-beta and transporting the cargo into the nucleolus. Surprisingly, similar arginine-rich signals identified in RASSF1C and RASSF2 interact with importin-alpha and transport the heterologous cytoplasmic proteins to the nucleus. Interestingly, mutation of arginine residues within these nuclear targeting signals prevented interaction of Ras effector proteins with respective transport receptors and abolished their nuclear translocation. These results provide evidence for the first time that arginine-rich signals are able to recognize different nuclear import receptors and transport the RASSF proteins into distinct sub-cellular compartments. In addition, our data suggest that the nuclear localization of RASSF5 is critical for its cell growth control activity. Together, these data suggest that the transport of Ras effector superfamily proteins into the nucleus/nucleolus may play a vital role in modulating Ras-mediated cell proliferation during tumorigenesis.
- Subjects :
- Active Transport, Cell Nucleus
Adaptor Proteins, Signal Transducing
Amino Acid Motifs
Amino Acid Sequence
Animals
Apoptosis Regulatory Proteins
COS Cells
Chlorocebus aethiops
HeLa Cells
Humans
Molecular Sequence Data
Monomeric GTP-Binding Proteins chemistry
Nuclear Localization Signals chemistry
Protein Binding
Proteins chemistry
Sequence Homology, Amino Acid
Tumor Suppressor Proteins chemistry
beta Karyopherins metabolism
Arginine metabolism
Cell Nucleus metabolism
Monomeric GTP-Binding Proteins metabolism
Proteins metabolism
Tumor Suppressor Proteins metabolism
alpha Karyopherins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2836
- Volume :
- 367
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 17320110
- Full Text :
- https://doi.org/10.1016/j.jmb.2007.01.026