Alteration of gene expression and protein solubility of the PI 5-phosphatase SHIP2 are correlated with Alzheimer's disease pathology progression.

A recent large genome-wide association study has identified EGFR (encoding the epidermal growth factor EGFR) as a new genetic risk factor for late-onset AD. SHIP2, encoded by INPPL1, is taking part in the signalling and interactome of several growth factor receptors, such as the EGFR. While INPPL1 has been identified as one of the most significant genes whose RNA expression correlates with cognitive decline, the potential alteration of SHIP2 expression and localization during the progression of AD remains largely unknown.

Loss of INPP5K attenuates IP-induced Ca responses in the glioblastoma cell line U-251 MG cells.

INPP5K (inositol polyphosphate 5-phosphatase K) is an endoplasmic reticulum (ER)-resident enzyme that acts as a phosphoinositide (PI) 5-phosphatase, capable of dephosphorylating various PIs including PI 4,5-bisphosphate (PI(4,5)P), a key phosphoinositide found in the plasma membrane. Given its ER localization and substrate specificity, INPP5K may play a role in ER-plasma membrane contact sites. Furthermore, PI(4,5)P serves as a substrate for phospholipase C, an enzyme activated downstream of extracellular agonists acting on Gq-coupled receptors or tyrosine-kinase receptors, leading to IP production and subsequent release of Ca from the ER, the primary intracellular Ca storage organelle.

Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs).

GISTs are sarcomas of the gastrointestinal tract often associated with gain-of-function mutations in KIT or PDGFRA receptor genes. While most GISTs initially respond to tyrosine kinase inhibitors, relapses due to acquired resistance frequently occur. The induction of ferroptosis, an iron-dependent form of non-apoptotic cell death, emerged as a novel therapeutic approach in cancers and remains poorly characterized in GISTs.

IRSp53 is a novel interactor of SHIP2: A role of the actin binding protein Mena in their cellular localization in breast cancer cells.

A tight control of the machineries regulating membrane bending and actin dynamics is very important for the generation of membrane protrusions, which are crucial for cell migration and invasion. Protein/protein and protein/phosphoinositides complexes assemble and disassemble to coordinate these mechanisms, the scaffold properties of the involved proteins playing a prominent role in this organization. The PI 5-phosphatase SHIP2 is a critical enzyme modulating PI(3,4,5)P, PI(4,5)P and PI(3,4)P content in the cell.

APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin.

The C-terminal variants G1 and G2 of apolipoprotein L1 (APOL1) confer human resistance to the sleeping sickness parasite Trypanosoma rhodesiense, but they also increase the risk of kidney disease. APOL1 and APOL3 are death-promoting proteins that are partially associated with the endoplasmic reticulum and Golgi membranes. We report that in podocytes, either APOL1 C-terminal helix truncation (APOL1Δ) or APOL3 deletion (APOL3KO) induces similar actomyosin reorganization linked to the inhibition of phosphatidylinositol-4-phosphate [PI(4)P] synthesis by the Golgi PI(4)-kinase IIIB (PI4KB).

Phosphoinositide 5-phosphatases SKIP and SHIP2 in ruffles, the endoplasmic reticulum and the nucleus: An update.

Phosphoinositides (PIs) are phosphorylated derivatives of phosphatidylinositol. They act as signaling molecules linked to essential cellular mechanisms in eukaryotic cells, such as cytoskeleton organization, mitosis, polarity, migration or invasion. PIs are phosphorylated and dephosphorylated by a large number of PI kinases and PI phosphatases acting at the 5-, 4- and 3- position of the inositol ring.

Altered chondrocyte differentiation, matrix mineralization and MEK-Erk1/2 signaling in an INPPL1 catalytic knock-out mouse model of opsismodysplasia.

Opsismodysplasia (OPS) is a rare but severe autosomal recessive skeletal chondrodysplasia caused by inactivating mutations in the Inppl1/Ship2 gene. The molecular mechanism leading from Ship2 gene inactivation to OPS is currently unknown. Here, we used our Ship2 mouse expressing reduced amount of a catalytically-inactive SHIP2 protein and a previously reported SHIP2 inhibitor to investigate growth plate development and mineralization in vivo, ex vivo and in vitro.

Potentiation of imatinib by cilostazol in sensitive and resistant gastrointestinal stromal tumor cell lines involves YAP inhibition.

Despite the introduction of tyrosine kinase inhibitors, gastrointestinal stromal tumors (GIST) resistance remains a major clinical challenge. We previously identified phosphodiesterase 3A (PDE3A) as a potential therapeutic target expressed in most GIST. The PDE3 inhibitor cilostazol reduced cell viability and synergized with the tyrosine kinase inhibitor imatinib (Gleevec™) in the imatinib-sensitive GIST882 cell line.

Lipid phosphatases SKIP and SHIP2 regulate fibronectin-dependent cell migration in glioblastoma.

Cell migration is an important process that occurs during development and has also been linked to the motility of cancer cells. Cytoskeleton reorganization takes place in the migration process leading to lamellipodia formation. Understanding the molecular underpinnings of cell migration is particularly important in studies of glioblastoma, a highly invasive and aggressive cancer type.

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

Sustained activation of extracellular signal-regulated kinase (ERK) drives pathologies caused by mutations in fibroblast growth factor receptors (FGFRs). We previously identified the inositol phosphatase SHIP2 (also known as INPPL1) as an FGFR-interacting protein and a target of the tyrosine kinase activities of FGFR1, FGFR3, and FGFR4. We report that loss of SHIP2 converted FGF-mediated sustained ERK activation into a transient signal and rescued cell phenotypes triggered by pathologic FGFR-ERK signaling.

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

Phosphoinositides (PIs) are recognized as major signaling molecules in many different functions of eukaryotic cells. PIs can be dephosphorylated by multiple phosphatase activities at the 5-, 4-, and 3- positions. Human PI 5-phosphatases belong to a family of 10 members.

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

Metastasis of breast cancer cells to distant organs is responsible for ∼50% of breast cancer-related deaths in women worldwide. SHIP2 (also known as INPPL1) is a phosphoinositide 5-phosphatase for phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2]. Here we show, through depletion of SHIP2 in triple negative MDA-MB-231 cells and the use of SHIP2 inhibitors, that cell migration appears to be positively controlled by SHIP2.

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

Inositol polyphosphate 5-phosphatases or phosphoinositide 5-phosphatases (PI 5-phosphatases) are enzymes that can act on soluble inositol phosphates and/or phosphoinositides (PIs). Several PI 5-phosphatases have been linked to human genetic diseases, in particular the Lowe protein or OCRL which is mutated in the Lowe syndrome. There are 10 different members of this family and 9 of them can use PIs as substrate.

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

The SH2 domain containing inositol phosphatase 2 (SHIP2) dephosphorylates PI(3,4,5)P3 to generate PI(3,4)P2, a lipid involved in the control of cell migration and adhesion. The INPPL1 gene that encodes SHIP2 has been found to be mutated in several cases of opsismodysplasia (OPS), a rare autosomal recessive chondrodysplasia characterized by growth plate defects and delayed bone maturation. Reported mutations often result in premature stop codons or missense mutations in SHIP2 catalytic domain.

The type III effector IpgD recodes Ca signals during invasion of epithelial cells.

The role of second messengers in the diversion of cellular processes by pathogens remains poorly studied despite their importance. Among these, Ca virtually regulates all known cell processes, including cytoskeletal reorganization, inflammation, or cell death pathways. Under physiological conditions, cytosolic Ca increases are transient and oscillatory, defining the so-called Ca code that links cell responses to specific Ca oscillatory patterns.

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

We previously identified phosphodiesterase 3A (PDE3A) as a marker for interstitial cells of Cajal (ICC) in adult mouse gut. However, PDE3A expression and function during gut development and in ICC-derived gastrointestinal stromal tumors (GIST) remained unknown. Here we found that PDE3A was expressed throughout ICC development and that ICC density was halved in PDE3A-deficient mice.

Astrocytic IP/Ca Signaling Modulates Theta Rhythm and REM Sleep.

Rapid eye movement (REM) sleep onset is triggered by disinhibition of cholinergic neurons in the pons. During REM sleep, the brain exhibits prominent activity in the 5-8 Hz (theta) frequency range. How REM sleep onset and theta waves are regulated is poorly understood.

SHIP2: Structure, Function and Inhibition.

SHIP2 is a phosphatase that acts at the 5-position of phosphatidylinositol 3,4,5-trisphosphate. It is one of several enzymes that catalyse dephosphorylation at the 5-position of phosphoinositides or inositol phosphates. SHIP2 has a confirmed role in opsismodysplasia, a disease of bone development, but also interacts with proteins involved in insulin signalling, cytoskeletal function (thus having an impact on endocytosis, adhesion, proliferation and apoptosis) and immune system function.

IPMK and β-catenin mediate PLC-β1-dependent signaling in myogenic differentiation.

In previous studies, we have reported that phospholipase C (PLC)-β1 plays a crucial role in myogenic differentiation and we determined the importance of its catalytic activity for the initiation of this process. Here we define the effectors that take part to its signaling pathway. We show that the Inositol Polyphosphate Multikinase (IPMK) is able to promote myogenic differentiation since its overexpression determines the up-regulation of several myogenic markers.

The SHIP2 interactor Myo1c is required for cell migration in 1321 N1 glioblastoma cells.

The phosphoinositide 5-phosphatases consist of several enzymes that have been shown to modulate cell migration and invasion. SHIP2, one family member, is known to interact with growth factor receptors and cytoskeletal proteins. In a human model of glioblastoma 1321 N1 cells, we recently identified Myo1c as a new interactor of SHIP2.

Specific expression and function of inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) in wild type and knock-out mice.

Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is the last identified member of the inositol 1,4,5-trisphosphate 3-kinases family which phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate. Although expression and function of the two other family members ITPKA and ITPKB are rather well characterized, similar information is lacking for ITPKC. Here, we first defined the expression of Itpkc mRNA and protein in mouse tissues and cells using in situ hybridization and new antibodies.