Hic-5 communicates between focal adhesions and the nucleus through oxidant-sensitive nuclear export signal.
hic-5 was originally isolated as an H(2)O(2)-inducible cDNA clone whose product was normally found at focal adhesions. In this study, we found that Hic-5 accumulated in the nucleus in response to oxidants such as H(2)O(2). Other focal adhesion proteins including paxillin, the most homologous to Hic-5, remained in the cytoplasm. Mutation analyses revealed that the C- and N-terminal halves of Hic-5 contributed to its nuclear localization in a positive and negative manner, respectively. After the finding that leptomycin B (LMB), an inhibitor of nuclear export signal (NES), caused Hic-5 to be retained in the nucleus, Hic-5 was demonstrated to harbor NES in the N-terminal, which was sensitive to oxidants, thereby regulating the nuclear accumulation of Hic-5. NES consisted of a leucine-rich stretch and two cysteines with a limited similarity to Yap/Pap-type NES. In the nucleus, Hic-5 was suggested to participate in the gene expression of c-fos. Using dominant negative mutants, we found that Hic-5 was actually involved in endogenous c-fos gene expression upon H(2)O(2) treatment. Hic-5 was thus proposed as a focal adhesion protein with the novel aspect of shuttling between focal adhesions and the nucleus through an oxidant-sensitive NES, mediating the redox signaling directly to the nucleus.
Shibanuma
Motoko
M
Department of Microbiology, Showa University School of Pharmaceutical Sciences, Hatanodai 1-5-8, Shinagawa-ku, Tokyo, Japan. smotoko@pharm.showa-u.ac.jp
Kim-Kaneyama
Joo-ri
JR
Ishino
Keiko
K
Sakamoto
Nobuko
N
Hishiki
Tomoko
T
Yamaguchi
Kaeko
K
Mori
Kazunori
K
Mashimo
Jun-ichi
J
Nose
Kiyoshi
K
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D051379:Mice; D008969:Molecular Sequence Data; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction; D051419:Paxillin; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D016596:Vinculin / Q000378:metabolism
D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D016877:Oxidants; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D021382:Protein Sorting Signals; D016760:Proto-Oncogene Proteins c-fos; C496062:Pxn protein, mouse; C508960:TGFB1 protein, human; C490351:TGFB1I1 protein, human; C508961:Tgfb1 protein, mouse; C090090:Tgfb1i1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016596:Vinculin; D006861:Hydrogen Peroxide