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Vol. 19, Issue 4, 1378-1390, April 2008

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Disruption of c-Jun Reduces Cellular Migration and Invasion through Inhibition of c-Src and Hyperactivation of ROCK II Kinase

Xuanmao Jiao^*, Sanjay Katiyar^*,, Manran Liu^*,, Susette C. Mueller, Michael P. Lisanti^*, Anping Li^*, Timothy G. Pestell^*, Kongming Wu^*, Xiaoming Ju^*, Zhiping Li^*, Erwin F. Wagner, Tatsuo Takeya^||, Chenguang Wang^*,¶, and Richard G. Pestell^*,¶

Departments of *Cancer Biology and ^¶Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; Georgetown University, Lombardi Comprehensive Cancer Center, Washington, DC 20057; Spanish Cancer Research Center (CNIO), E-28029 Madrid, Spain; and ^||Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan

Submitted August 3, 2007; Revised November 28, 2007; Accepted January 10, 2008
Monitoring Editor: John Cleveland

The spread of metastatic tumors to different organs is associated with poor prognosis. The metastatic process requires migration and cellular invasion. The protooncogene c-jun encodes the founding member of the activator protein-1 family and is required for cellular proliferation and DNA synthesis in response to oncogenic signals and plays an essential role in chemical carcinogenesis. The role of c-Jun in cellular invasion remains to be defined. Genetic deletion of c-Jun in transgenic mice is embryonic lethal; therefore, transgenic mice encoding a c-Jun gene flanked by LoxP sites (c-jun^f/f) were used. c-jun gene deletion reduced c-Src expression, hyperactivated ROCK II signaling, and reduced cellular polarity, migration, and invasiveness. c-Jun increased c-Src mRNA abundance and c-Src promoter activity involving an AP-1 site in the c-Src promoter. Transduction of c-jun^–/– cells with either c-Jun or c-Src retroviral expression systems restored the defective cellular migration of c-jun^–/– cells. As c-Src is a critical component of pathways regulating proliferation, survival, and metastasis, the induction of c-Src abundance, by c-Jun, provides a novel mechanism of cooperative signaling in cellular invasion.

These authors contributed equally to this work.

Address correspondence to: Richard G. Pestell (Richard.Pestell{at}jefferson.edu)

Abbreviations used: AP-1, activator protein 1; Cas, Crk-associated substrate; IRM, interferential reflection microscopy; JNK, c-Jun kinase; LIMK, LIM kinase; MLCK, myosin light-chain kinase; ZRP-1, zyxin-related protein 1.