• E-mail :[email]
  • Phone : +33 4 86 97 72 57
  • Location : Marseille, France
Last update 2012-07-13 09:29:52.374

Michael SEBBAGH PhD in molecular pharmacology

Course and current status

In 1999, Dr. Sebbagh joined Dr. Jacqueline Bréard’s team as a PhD student, collectively supervised by Pr. Eric Solary, at Paris-Sud University (INSERM U461, Chatenay-Malabry, France). During his thesis (1999-2003), he was interested in the mechanisms of program cell death and especially in morphological modifications that occurs at the onset of it. He investigated cell contractility that was an emerging field, outside cell migration, unexplored in the apoptosis process. His work uncovered the molecular mechanism responsible for the transient membrane blebbing which is one of the earliest observable apoptotic morphological modifications. The novelty of these works was not only in the molecular explanation of the morphological changes initially observed by Wyllie when he first described apoptosis in 1972, but also, by the notion that their dynamics is a part of the efficiency of the apoptotic program and this either during the initiation or in the execution phases.

He continued to work in cell contractility field and joined Pr. Martin Alexander Schwartz’s lab (University of Virginia, Charlottesville VA, USA) as research associate (2004-2006). He was in charged of evaluating the function of contractibility in the apico-basal cell polarity establishment. He chose an original angle of research through the studying involvement of LKB1 kinase, which was just involved in cell polarity, and E-cadherin a major player in epithelial cell polarity establishment.

To achieve this program, in 2007 he initiated a trans-Atlantic collaboration by joining the CRCM (INSERM UMR1068, Marseille) in Pr. Jean-Paul Borg’s lab which is specialized in epithelial cell polarity and related studies, through a fellowship from the “Ligue Nationale Contre le Cancer”. Since then, he is developing the LKB1 project autonomously within the framework of the Pr Borg’s team. New concepts and new results in this field have allowed him to get an INSERM tenure position as investigator in 2009.

Scientific summary

The serine threonine kinase LKB1 is ubiquitously expressed and conserved throughout evolution. In humans, LKB1 is causally linked to the Peutz-Jeghers syndrome (PJS), an autosomal dominant inherited disorder characterized by melanocytic macules of the lips and multiple gastrointestinal hamartomatous polyps. PJS patients have a high risk of developing malignant tumours, including breast and gastrointestinal cancers, due to lkb1 biallelic loss. Moreover lkb1 is also one of the most commonly mutated gene in sporadic human lung cancers (15–35% of non-small cell lung carcinoma) and 20% of cervical carcinomas. These observations have led to classify lkb1 as a tumour suppressor gene.

Structurally, LKB1 is composed of a serine-threonine kinase domain with poor catalytic activity. Full LKB1 kinase activity requires its interaction with STRAD (STE-20 Related ADaptator) protein which is ubiquitously expressed pseudo-kinase. A third protein, MO25, interacts with STRAD protein and stabilizes the LKB1/STRAD interaction. Active LKB1 is therefore a tripartite complex (1:1:1) referred as the LKB1 complex.

At the cellular level, the LKB1 complex activity has pleiotropic effects, being implicated in cell cycle arrest, apoptosis, energy metabolism as well as in directional cell migration and apico-basal cell polarity. To exert all these cellular effects, the LKB1 complex phosphorylates and activates 14 members of the AMPK family kinase. The AMPK kinase, a prototypical family member regulates cell energy metabolism, and cell growth. It is of particular interest to understand the mechanisms that participate to regulation of AMPK since this protein kinase regulates, in part, the cellular metabolism by repressing the mTOR pathways often up-regulated in tumors. Although the role of the LKB1 complex as metabolic regulator through AMPK activation is well established, it is likely that the large range of LKB1 substrates are implicated in many other functions. However, little information have been gathered about the mechanism of regulation of this complex.

Recently, we published results suggesting that the LKB1 complex is constitutively active in cells and that its regulation is in fact the result of its intracellular localization, allowing a spatiotemporal proximity with a subset of specific substrates. Through classical and innovative strategies, our project aims to better understand the LKB1 complex regulation and identify potential new functions.

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