LKB1 : a master regulator of cell polarity

Abstract

The research described in this thesis focuses on the LKB1 serine/threonine kinase. LKB1 is a tumor suppressor protein, which is found mutated in the germline of Peutz-Jeghers syndrome (PJS) patients. PJS patient typically develop gastrointestinal hamartomas and show abnormal pigmentation. In addition that are at risk for the development of several rare malignancies.

Our research on the LKB1 kinase was initiated in November 1999. At that time, LKB1 had just been classified as a tumor suppressor protein, but nothing was known about its biological role. Originally, our interest in the LKB1 tumor suppressor resulted from a yeast-two hybrid screen using β-catenin as a bait. In this assay, LKB1 was identified as a β-catenin binding partner. While this interaction later turned out to be false, the studies on the LKB1 kinase proceeded.

This thesis describes the discovery of LKB1 in endogenous complexes with the adaptor molecules STRAD and MO25 (Chapters 2&3). Detailed biochemical studies revealed that this complex formation is required for LKB1 activity and correct LKB1 cellular localization. Exploiting this observation, a cellular system was generated in which LKB1 could be activated by the controlled expression of STRAD (Chapter 4). Activated LKB1 was subsequently shown to rapidly impose the execution of a full polarization program in a cell-autonomous fashion. The discussion (Chapter 5) illustrates how the work of different laboratories worldwide over the past six years has contributed to the current understanding of the tumor suppressor kinase LKB1.