The p21-activated protein kinase (Pak) family of enzymes regulates the shape and polarity of cells. Control of cell shape is a vital process underlying events such as cell mi-gration, nerve impulse transmission, response to nutrients, and metastasis. Abnormalities in these processes underly many important human diseases, including most malignancies. Thus, it is crucial to understand how members of this emerging family of protein kinases are regulated and uncover their targets within the cell. We have isolated multiple forms of Pak from man and fission yeast. These two organisms offer distinct experimental advantages which will be exploited to achieve the specific aims of this project. In mammalian cells, the regulation of Pak. by growth factors and Ras- related p21 GTPases will be examined, as well as Pak~s interactions with other known signaling proteins. Mammalian cells will also be used to study the signaling pathway by which Pak regulates cell shape and polarity, and the role of this kinase in mediating stress responses. In fission yeast, genetic techniques will brought to bear to identify downstream targets of Pak. Achieving the aims set forth in this proposal will shed light on a fundamental biologic property: the mechanisms by which cells establish and maintain their shape. By these studies, we also hope to better define the relationship between the control of cell shape and division. Understanding the molecular basis for this phenomenon is not only of intrinsic scientific interest but is also likely to be relevant to important human diseases such as metastatic cancer.
| Pacheco, Almudena; Chernoff, Jonathan (2010) Group I p21-activated kinases: emerging roles in immune function and viral pathogenesis. Int J Biochem Cell Biol 42:13-6 |
| Flaiz, Christine; Chernoff, Jonathan; Ammoun, Sylwia et al. (2009) PAK kinase regulates Rac GTPase and is a potential target in human schwannomas. Exp Neurol 218:137-44 |
| ten Klooster, Jean Paul; Jaffer, Zahara M; Chernoff, Jonathan et al. (2006) Targeting and activation of Rac1 are mediated by the exchange factor beta-Pix. J Cell Biol 172:759-69 |
| Beeser, Alexander; Jaffer, Zahara M; Hofmann, Clemens et al. (2005) Role of group A p21-activated kinases in activation of extracellular-regulated kinase by growth factors. J Biol Chem 280:36609-15 |
| Leisner, Tina M; Liu, Mingjuan; Jaffer, Zahara M et al. (2005) Essential role of CIB1 in regulating PAK1 activation and cell migration. J Cell Biol 170:465-76 |
| Reynolds, Lucinda F; de Bettignies, Carine; Norton, Trisha et al. (2004) Vav1 transduces T cell receptor signals to the activation of the Ras/ERK pathway via LAT, Sos, and RasGRP1. J Biol Chem 279:18239-46 |
| Cotteret, Sophie; Jaffer, Zahara M; Beeser, Alexander et al. (2003) p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Mol Cell Biol 23:5526-39 |
| Cheung, Wang L; Ajiro, Kozo; Samejima, Kumiko et al. (2003) Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell 113:507-17 |
| Xiao, Guang-Hui; Beeser, Alexander; Chernoff, Jonathan et al. (2002) p21-activated kinase links Rac/Cdc42 signaling to merlin. J Biol Chem 277:883-6 |
| Thiel, Debra A; Reeder, Melissa K; Pfaff, Amanda et al. (2002) Cell cycle-regulated phosphorylation of p21-activated kinase 1. Curr Biol 12:1227-32 |
Showing the most recent 10 out of 16 publications
