Isabelle Pirson

Our research

Docking properties of the phosphatidylinositol 5-phosphatase type II (SHIP2) a negative regulator of the PI3 kinase cascade

Phosphoinositides (PI) are crucial for recruitment and regulation of proteins in different cellular membranes and play essential role in cell signaling and membrane dynamics. Among them PI(3,4,5)P3, important for cellular survival, is produced by the PI 3 kinase (PI3K) the most frequently known activated aberrant pathway in human cancers. SHIP2 contributes to the negative regulation of this pathway by converting PI(3,4,5)P3 in PI(3,4)P2, another important PI involved in cell adhesion and migration. The PI(3,4,5)P3 phosphatase activity of SHIP2 is not the only functional element of the protein as it is also involved in a network of protein-protein interactions that could influence its cellular location and indirectly its activity.
In humans, gene mutations of SHIP2 cause opsismodysplasia, a pathology of skeletal bone formation (Below et al., 2013; Huber et al., 2013). In living cells, SHIP2 appears to be involved in developmental processes (proliferation, adhesion and cell migration) and in metabolic functions (insulin signaling and obesity).

Using two-hybrid screening, we previously identified potential proteic partners for SHIP2 that suggest a role of the protein in cell physiology. Among the identified partners c-Cbl, Intersectin (ITSN), JIP1 or APS are involved in vesicular traffic mechanisms, adhesion processes or EGF or insulin receptor regulation (Xie et al., 2013). Studying the physiological and cellular roles of SHIP2, particular interest has been attached to a new potential regulation mode of SHIP2 : ubiquitination (De Schutter et al., 2009). SHIP2 is notably the object of phosphorylations on tyrosine, serine and threonine whose impact on its cellular localization has already been well documented. We have shown that SHIP2 can also be the subject of mono-ubiquitination, which is particularly important in trafficking and endocytotic mechanisms.

Faced with all these converging results that suggest an implication of SHIP2 in the regulation of receptor endocytosis and cellular adhesion and migration, we continue to attempt to better define the molecular mechanisms controlled by SHIP2 as a scaffold protein and its role in the ubiquitination signaling pathways.

New causal genes in recessive neuro-developmental rare diseases: micro- and hydro- cephaly.

Many genes causing monogenic rare diseases remain to be discovered. Identifying the genes causing rare diseases is fundamental to improve the diagnostic and therapeutic tools. It also contributes to unravel the molecular role of these genes whose function is often still unknown. Many rare diseases that affect children of healthy parents are autosomal recessive genetic disorders. Patients from consanguineous families, which are often composed of several affected individuals, help to the identification of the genes causing these pathologies through the presence of homozygous rare variants in their genome.
Exome sequencing allowed the comparison of genomic alterations between affected and unaffected children and their parents, increasing the power of identification of variants in candidate genes.

Our main research interest is the study of families with neuro-developmental diseases: primary microcephaly and primary congenital hydrocephalus. We therefore performed exome analyzes in two cohorts of patients with these pathologies and used the zebrafish model to validate the causality of several identified candidate genes.

We identified CASC5 as the causal gene of recessive microcephaly in a family of Moroccan origin. This mutation results in a splicing defect generating of a premature stop codon in the protein that belongs to the KMN network of kinetochore and is necessary for the attachment of appropriate microtubules to the centromere of the chromosomes and to the assembly of the mitotic spindle (Genin et al., 2012). A mutation identified in an M1 subunit of AP4, an intracellular transport protein of the neuron, allowed to extend the mutation phenotype of this gene to severe microcephaly (Duerinckx et al., 2018). Two new variants causing primary hydrocephaly have also been identified in CCDC88C, a partner of Disheveled regulator of the Wnt signaling cascade (Drielsma et al., 2012).
We are now involved in the molecular characterization of the mechanisms of action of new candidate genes causing hydrocephalus in the Zebrafish as a model. We test the causality of our candidates using the CRISPR/Cas9 invalidation technique in zebrafish in collaboration with
Pr Costagliola’s Lab.

Group members

Isabelle Pirson, PI
(ilpirson@ulb.ac.be)
Phone #: +32 (0) 2 555 41 37

Mathieu Antoine (PhD student),

Chantal Degraef (Technician)

Alumni

Isabelle Vandenbroere
Christine Jacobs
Tatjana Arsenijevic
Séverine Steuve
Sheela Onnockx
Jingwei Xie
Julie DeSchutter

Publications

Publications

Xie, J., Erneux, C., & Pirson, I. (2013). How does SHIP1/2 balance PtdIns(3,4)P2 and does it signal independently of its phosphatase activity? BioEssays, 35(8), 733-743. doi:10.1002/bies.201200168
Igoillo Esteve, M., Genin, A., Lambert, N., Désir, J., Pirson, I., Abdulkarim, B., Simonis, N., Drielsma, A., Marselli, L., Marchetti, P., Vanderhaeghen, P., Eizirik, D. L., Wuyts, W., Julier, C., Chakera, A. J., Ellard, S., Hattersley, A. T., Abramowicz, M., & Cnop, M. (2013). tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in human. PLoS genetics, 9. doi:10.1371/journal.pgen.1003888

Genin, A., Désir, J., Lambert, N., Biervliet, M., Van Der Aa, N., Pierquin, G., Killian, A., Tosi, M., Urbina, M., Lefort, A., Libert, F., Pirson, I., & Abramowicz, M. (2012). Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Human molecular genetics, 21(24), 5306-5317. doi:10.1093/hmg/dds386

Drielsma, A., Jalas, C., Simonis, N., Désir, J., Simanovsky, N., Pirson, I., Elpeleg, O., Abramowicz, M., & Edvardson, S. (2012). Two novel CCDC88C mutations confirm the role of DAPLE in autosomal recessive congenital hydrocephalus. Journal of medical genetics, 49(11), 708-712. doi:10.1136/jmedgenet-2012-101190

Burniat, A., Pirson, I., Vilain, C., Kulik, W., Afink, G., Moreno Reyes, M. R., Corvilain, B., & Abramowicz, M. (2012). Iodotyrosine deiodinase defect identified via genome-wide approach. The Journal of clinical endocrinology and metabolism, 97(7), E1276-E1283. doi:10.1210/jc.2011-3314
Erneux, C., Elong Edimo, W., Deneubourg, L., & Pirson, I. (2011). SHIP2 multiple functions: a balance between a negative control of PtdIns(3,4,5)P₃ level, a positive control of PtdIns(3,4)P₂ production, and intrinsic docking properties. Journal of cellular biochemistry, 112(9), 2203-2209. doi:10.1002/jcb.23146

Azizieh, N.-R., Orduz Perez, D., Van Bogaert, P., Bouschet, T., Rodriguez, W., Schiffmann, S. N., Pirson, I., & Abramowicz, M. (2011). Progressive myoclonic epilepsy-associated gene KCTD7 is a regulator of potassium conductance in neurons. Molecular neurobiology, 44(1), 111-121. doi:10.1007/s12035-011-8194-0

Vilain, C., Rens, C., Aeby, A., Balériaux, D., Van Bogaert, P., Remiche, G., Smet, J., Van Coster, R., Abramowicz, M., & Pirson, I. (2011). A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome. Clinical genetics, 82(3), 264-270. doi:10.1111/j.1399-0004.2011.01743.x

De Schutter, J., Guillabert, A., Imbault, V., Degraef, C., Erneux, C., Communi, D., & Pirson, I. (2009). SHIP2 (SH2 domain-containing inositol phosphatase 2) SH2 domain negatively controls SHIP2 monoubiquitination in response to epidermal growth factor. The Journal of biological chemistry, 284(52), 36062-36076. doi:10.1074/jbc.M109.064923

Onnockx, S., Xie, J., Degraef, C., Erneux, C., & Pirson, I. (2009). Insulin increase in MAP kinase phosphorylation is shifted to early time-points by overexpressing APS, while Akt phosphorylation is not influenced. Experimental cell research, 315(15), 2479-2486. doi:10.1016/j.yexcr.2009.06.006
Montagut, G., Onnockx, S., Vaqué, M., Bladé, C., Blay, M., Fernández-Larrea, J., Pujadas, G., Salvadó, M. J., Arola, L., Pirson, I., Ardévol, A., & Pinent, M. (2009). Oligomers of grape-seed procyanidin extract activate the insulin receptor and key targets of the insulin signaling pathway differently from insulin. Journal of nutritional biochemistry. doi:10.1016/j.jnutbio.2009.02.003

Xie, J., Vandenbroere, I., & Pirson, I. (2008). SHIP2 associates with intersectin and recruits it to the plasma membrane in response to EGF. FEBS letters, 582(20), 3011-3017. doi:10.1016/j.febslet.2008.07.048

Xie, J., Onnockx, S., Vandenbroere, I., Degraef, C., Erneux, C., & Pirson, I. (2008). The docking properties of SHIP2 influence both JIP1 tyrosine phosphorylation and JNK activity. Cellular signalling, 20(8), 1432-1441. doi:10.1016/j.cellsig.2008.03.010

Onnockx, S., De Schutter, J., Blockmans, M., Xie, J., Jacobs, C., Vanderwinden, J.-M., Erneux, C., & Pirson, I. (2008). The association between the SH2-containing inositol polyphosphate 5-Phosphatase 2 (SHIP2) and the adaptor protein APS has an impact on biochemical properties of both partners. Journal of cellular physiology, 214(1), 260-272. doi:10.1002/jcp.21193