Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire

Inositol Signalling Group

Introduction
 
 Image1 erneux
 

 

Inositol trisphosphate 3-kinase A isoenzyme (Itpka) localisation in CHO cells (stably transfected with humam Itpka; F De Smedt)
 
 
  Nath Paternotte
 
 

SHIP2 and Vinexin alpha (a cytoskeletal protein) localisation in COS-7 transfected cells (N. Paternotte)
 
 

 if kit pten p14 mice bis

 

 

 

 PTEN-ir (in red) and Kit-ir (in green) in P14 antrum of KIT K641E homozygous mice, a mouse model of gastro intestinal stromal tumours (GIST) knock-in mice, resulting in the substitution of a Lys by Glu at position 641 of Kit (L. Deneubourg and J.M.Vanderwinden)
 
 
WilliamsN1pS132rSC35gx63NA1
 
 
  
SHIP2 phosphorylated on Ser 132 (pSHIP2 S132)-ir (in red) and SC-35 (in green) in human astrocytoma cells (William's Elong Edimo)

 

 

 
 
The inositol building block
 
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Myo-inositol phosphates, soluble and lipidic molecules, play a fundamental role in cell regulation and membrane dynamics. Phosphatidylinositol, a membrane phospholipid, can be reversibly phosphorylated at the 3, 4 and 5 positions of myo-inositol to generate phosphoinositides (PIs) (seven are currently known in mammalian cells). Phosphoinositides play a fundamental role in cell physiology, signalling and physiopathology (Blero et al., 2007). In particular, cell growth in normal and cancer cells is often controlled by a PI 3-kinase activity. Activation of this enzymatic reaction (i.e. class I PI 3-kinase) leads to PI(3,4,5)P3 formation and this influences cell growth, cell cycle entry, cell survival and motility which are key elements in tumorigenesis.
Our interest in this metabolism started with the cloning of a series of inositol polyphosphate 5-phosphatase and Ins(1,4,5)P3 3-kinases. The first protein cloned was “type I Ins(1,4,5)P3 5-phosphatase” (Verjans et al., 1994) followed by the SH2 domain containing inositol 5-phosphatases SHIP1 and SHIP2 (Drayer et al., 1996;Pesesse et al., 1997;Pesesse et al., 2001). The substrate of SHIP1/2 is PI(3,4,5)P3 and the product of the reaction is PI(3,4)P2. Both PIs are able to bind to PKB and PDK1 PH domains and to facilitate PDK1 phosphoylation of PKB in vitro. SHIP1/2 are very much studied due to their implication in immune response, myeloid cell survival for SHIP1 and developmental aspects and the control of obesity for SHIP2 (Clement et al., 2001;Huber et al., 1999;Liu et al., 1999; Dubois et al., 2012). In addition, SHIP1/2 implication in human cancer has been strongly suggested next to the established tumor suppressor PTEN (see Erneux et al., 2011 Journal of Cellular Biochemistry  Vol 112, 9, 2203-2209, for review).

The goal of our laboratory is to understand why phosphatases and kinases that act on inositol phosphates and phosphoinositides are critical in signalling, particularly in cancer cells. The way these enzymes are regulated and/or participate in non-enzymatic properties but rather through docking properties is another aspect of our research.

Pathology:
Lowe Syndrome, Dent Disease, Cancer, Diabetes, Down syndrome, Alzheimer Disease and Opsismodysplesia are among human diseases resulting from germline or somatic mutations in genes encoding the PI kinases and phosphatases.
 
Key words: cancer, intracellular signalling, cyclic nucleotides, inositol phosphates, phosphoinositides, phosphatases and kinases.

Projects:
The role of SHIP1/2 Ser/Thr/Tyr phosphorylation in signalling, particularly in nuclear signalling
The role of inositol phosphate multikinase (Ipmk) in neuronal differentiation.
The role of SHIP1/2 in cytoskeletal organisation and signalling.
The role of SHIP2 and PTEN in a model of gastrointestinal stromal tumors (this study is conducted in collaboration with Dr. Jean-Marie Vanderwinden).
The identification of novel inositol phosphatase inhibitors (in collaboration with Drs Steve Mills and Barry Potter).

Lab members
:  Christophe Erneux, Colette Moreau, William's Elong Edimo (Cameroon), Sandra Koenig, Somadri Ghosh (India).

Alumni:
Dominique Couchie, Françoise Miot, Kazunaga Takazawa (Japan), Anne Delvaux, Benoît Verjans, Valérie Vanweyenberg, David Communi, Florence De Smedt, Xavier Pesesse, Valérie Dewaste, Nathalie Paternotte, Sylvie Giuriato (France), Lyndsay A Drayer (Holland), Daniel Blero, Katrien Backers, Jing Zhang (China), Fabrice Vandeput, Alexandre Leyman, Laurence Deneubourg, Xiao-Jun Choi ...

Contact
: Christophe Erneux email: Cette adresse e-mail est protégée contre les robots spammeurs. Vous devez activer le JavaScript pour la visualiser. ;phone # 32 2 555 4162 (4161). 
 
 

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