REGULATION OF P21-ACTIVATED KINASES

Institute For Cancer Research, Philadelphia PA

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Abstract

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.