Metabolism of phosphoinositides, ULB

   

 

 

 

 

GROUP LEADER

Christophe ERNEUX

 

Myo-inositol phosphates, soluble and lipid molecules, play fundamental functions 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 PIs are known in mammalian cells. PIs play fundamental roles in cell physiology, signaling and physiopathology (Blero et al., 2007). Moreover, the phosphoinositide (PI) 3-kinase (PI3K) pathway is one of the most frequently mutated signaling pathways in cancer being actively pursued today as a therapeutic target. However, resistance to inhibitors to PI3K due to compensatory signaling and genomic changes have emerged, suggesting the need for the use of inhibitors in combination with novel strategies and targets. The role of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3), the product of PI3K is fundamental in cancer research and often considered as “oncogenic” but other PIs such as phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) are also critical signal molecules, particularly in the control of cell adhesion, migration or invasion.

Our interest in the PI metabolism started with the cloning of a series of inositol polyphosphate 5-phosphatase and Ins(1,4,5)P3 3-kinases (the enzymes that phosphorylate Ins(1,4,5)P3 to Ins(1,3,4,5)P4).

cDNAs encoding INPP5A, Itpka, b and c followed by the SH2 domain containing inositol 5-phosphatases SHIP1 and SHIP2 have been cloned. 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 phosphorylation 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 for SHIP2 (Clement et al., 2001; Huber 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 role of PTEN (Erneux et al., 2011).

The current goal of our laboratory is to define the oncogenic and anti-oncogenic function of PI 5-phosphatases in cancer cells particularly in glioblastoma and breast cancer. The way these enzymes are regulated and/or participate in non-enzymatic properties but rather through docking properties is another aspect of our research.

Group Web Page

 

Important publications

 

The inositol phosphatase SHIP2 enables sustained ERK activation downstream of FGF receptors by recruiting Src kinases

Science Signaling 2018

 

The impact of PI 5-phosphatases on phosphoinositides in cell function and human disease

J. Lipid Res.(in press) 2018

 

Inhibition of SHIP2 activity inhibits cell migration and could prevent metastasis in breast cancer cells

J Cell Science 2018

 

Phosphoinositide 5-phosphatase activities control cell motility in glioblastoma: Two phosphoinositides PI(4,5)P2 and PI(3,4)P2 are involved

Advances in Biological Regulation 2018

 

Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects

Human Mutation 2017

 

The Shigella type III effector IpgD recodes Ca2+ signals during invasion of epithelial cells

Embo J 2017

 

Phosphodiesterase 3A: a new player in development of interstitial cells of Cajal and a prospective target in gastrointestinal stromal tumors (GIST)

Oncotarget 2017

 

Astrocytic IP3/Ca2+ Signaling Modulates Theta Rhythm and REM Sleep

Front. Neural Circuits 2017