Requirement of activated Cdc42-associated kinase for survival of v-Ras-transformed mammalian cells.
Activated Cdc42-associated kinase (ACK) has been shown to be an important effector molecule for the small GTPase Cdc42. We have shown previously an essential role for Cdc42 in the transduction of Ras signals for the transformation of mammalian cells. In this report, we show that the ACK-1 isoform of ACK plays a critical role in transducing Ras-Cdc42 signals in the NIH 3T3 cells. Overexpression of a dominant-negative (K214R) mutant of ACK-1 inhibits Ras-induced up-regulation of c-fos and inhibits the growth of v-Ras-transformed NIH 3T3 cells. Using small interfering RNA, we knocked down the expression of ACK-1 in both v-Ha-Ras-transformed and parental NIH 3T3 cells and found that down-regulation of ACK-1 inhibited cell growth by inducing apoptosis only in v-Ha-Ras-transformed but not parental NIH 3T3 cells. In addition, we studied the effect of several tyrosine kinase inhibitors and found that PD158780 inhibits the kinase activity of ACK-1 in vitro. We also found that PD158780 inhibits the growth of v-Ha-Ras-transformed NIH 3T3 cells. Taken together, our results suggest that ACK-1 kinase plays an important role in the survival of v-Ha-Ras-transformed cells, suggesting that ACK-1 is a novel target for therapies directed at Ras-induced cancer.
Nur-E-Kamal
Alam
A
Department of Pharmacology, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA. nurekasa@umdnj.edu
Zhang
Ailing
A
Keenan
Susan M
SM
Wang
Xin I
XI
Seraj
Jabed
J
Satoh
Takaya
T
Meiners
Sally
S
Welsh
William J
WJ
D000818:Animals; D002470:Cell Survival; D015536:Down-Regulation; D051379:Mice; D041681:NIH 3T3 Cells; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; D015689:Oncogene Protein p21(ras); D020764:cdc42 GTP-Binding Protein