This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nur-E-Kamal, A. Articles by Welsh, W. J. Search for Related Content PubMed PubMed Citation Articles by Nur-E-Kamal, A. Articles by Welsh, W. J.

---

Signaling and Regulation

Requirement of Activated Cdc42-Associated Kinase for Survival of v-Ras-Transformed Mammalian Cells

¹ Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey; ² Cancer Therapeutics Research Team, Johnson and Johnson Pharmaceutical Research and Development, Raritan, New Jersey; and ³ Division of Molecular Biology, Department of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Chuo-Ku, Kobe, Japan

Requests for reprints: Alam Nur-E-Kamal, Department of Pharmacology, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854. Phone: 732-235-0106; Fax: 732-235-4073. E-mail: nurekasa{at}umdnj.edu

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.

This article has been cited by other articles:

				N. P. Mahajan, Y. Liu, S. Majumder, M. R. Warren, C. E. Parker, J. L. Mohler, H. S. Earp, and Y. E. Whang Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation PNAS, May 15, 2007; 104(20): 8438 - 8443. [Abstract] [Full Text] [PDF]

				F. Shen, Q. Lin, Y. Gu, C. Childress, and W. Yang Activated Cdc42-associated Kinase 1 Is a Component of EGF Receptor Signaling Complex and Regulates EGF Receptor Degradation Mol. Biol. Cell, March 1, 2007; 18(3): 732 - 742. [Abstract] [Full Text] [PDF]

				K. Modzelewska, L. P. Newman, R. Desai, and P. J. Keely Ack1 Mediates Cdc42-dependent Cell Migration and Signaling to p130Cas J. Biol. Chem., December 8, 2006; 281(49): 37527 - 37535. [Abstract] [Full Text] [PDF]

				N. P. Mahajan, Y. E. Whang, J. L. Mohler, and H. S. Earp Activated Tyrosine Kinase Ack1 Promotes Prostate Tumorigenesis: Role of Ack1 in Polyubiquitination of Tumor Suppressor Wwox Cancer Res., November 15, 2005; 65(22): 10514 - 10523. [Abstract] [Full Text] [PDF]

				E. H. van der Horst, Y. Y. Degenhardt, A. Strelow, A. Slavin, L. Chinn, J. Orf, M. Rong, S. Li, L.-H. See, K. Q. C. Nguyen, et al. Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1 PNAS, November 1, 2005; 102(44): 15901 - 15906. [Abstract] [Full Text] [PDF]