Cdc42-dependent nuclear translocation of non-receptor tyrosine kinase, ACK.
Ras signals for the transformation of mammalian cells are apparently transduced through Rho GTPases. The Rho GTPase family member Cdc42 generates independent signals that regulate the rearrangement of the actin cytoskeleton and the transcription of genes. However, the molecular mechanism of signal transduction from Cdc42 to the nucleus remains to be understood. The non-receptor tyrosine kinases ACK-1 and ACK-2 have been found to bind specifically to Cdc42. In this paper we studied whether ACKs transduce Cdc42 signals to the nucleus directly, or through other cytoplasmic proteins. Using immunocytochemistry and Western blot analysis, we found a nuclear localization of ACKs in semi-confluent glioblastoma (U251) cells, as opposed to a cytosolic localization in confluent cells. In agreement with the nuclear localization, a putative nuclear export signal was identified in ACK-1 and ACK-2. Furthermore, the interaction of Cdc42 with ACKs was shown to be essential for the nuclear localization of ACKs. Overexpression of ACK42 (a Cdc42 binding domain of ACK) inhibited cell growth and movement, indicating that Cdc42 signals are transduced to the nucleus through ACKs. This is the first report providing evidence of a novel role for ACKs in transducing Cdc42 signals directly to the nucleus.
Ahmed
Ijaz
I
Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Calle
Yolanda
Y
Sayed
Mohammed A
MA
Kamal
Jabeen M
JM
Rengaswamy
Padmanabhan
P
Manser
Ed
E
Meiners
Sally
S
Nur-E-Kamal
Alam
A
D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D016716:PC12 Cells; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014945:Wound Healing; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; C498594:Tnk2 protein, mouse; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human; D020764:cdc42 GTP-Binding Protein; D020741:rho GTP-Binding Proteins