Phosphatidylinositol (PI) 4,5-bisphosphate (PI(4,5)P(2)) and its phosphorylated product PI 3,4,5-triphosphate (PI(3,4,5)P(3)) are two major phosphoinositides concentrated at the plasma membrane. Their levels, which are tightly controlled by kinases, phospholipases, and phosphatases, regulate a variety of cellular functions, including clathrin-mediated endocytosis and receptor signaling. In this...

OBJECTIVE Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by insulin resistance in the target tissue of insulin with insufficient insulin secretion in pancreatic β-cells. Src homology 2-containing 5'-inositol phosphatase 2 (SHIP2) is a lipid phosphatase that hydrolyzes PI3-kinase product PI(3,4,5)P3 to PI(3,4)P2, which contributes to the negative regulation of insulin signali...

The lipid phosphatase, PTEN (phosphatase and tensin homologue deleted on chromosome 10), is the product of a major tumour suppressor gene that antagonizes PI3K (phosphoinositide 3-kinase) signalling by dephosphorylating the 3-position of the inositol ring of PtdIns(3,4,5)P(3). PtdIns(3,4,5)P(3) is also metabolized by removal of the 5-phosphate catalysed by a distinct family of enzymes exemplifi...

SH2-domain-containing inositol phosphatase 2 (SHIP2) belongs to a small family of phosphoinositide 5-phosphatases that help terminate intracellular signaling initiated by activated receptor tyrosine kinases. Mammalian SHIP2 is viewed primarily as an attenuator of insulin signaling and has become a prominent candidate target for therapeutic agents that are designed to augment insulin signaling. ...

Amyloid-β (Aβ)-containing extracellular plaques and hyperphosphorylated tau-loaded intracellular neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease (AD). Although Aβ exerts neuropathogenic activity through tau, the mechanistic link between Aβ and tau pathology remains unknown. Here, we showed that the FcγRIIb-SHIP2 axis is critical in Aβ1-42-induced tau pathology. Fc...

Obesity is a well-recognized cancer risk factor. The increase in risk for colorectal, endometrial, breast and esophageal cancers associated with obesity ranges from 1.5to as much as 3-fold. Obese patients develop more aggressive cancers that are less responsive to treatment. Here, we review the available data on an obesity-linked gene, SH2-domaincontaining inositol 5-phosphatase-2 (SHIP2), in l...

Fc gammaRIIB are single-chain low-affinity receptors for IgG that bear an immunoreceptor tyrosine-based inhibition motif (ITIM) in their intracytoplasmic domain and that negatively regulate immunoreceptor tyrosine-based activation motif (ITAM)-dependent cell activation. In B cells, coaggregation of the B cell receptor (BCR) and Fc gammaRIIB leads to an inhibition of B cell activation. Inhibitor...

Genetic susceptibility to type 2 diabetes involves many genes, most of which are still unknown. The lipid phosphatase SHIP2 is a potent negative regulator of insulin signaling and sensitivity in vivo and is thus a good candidate gene. Here we report the presence of SHIP2 gene mutations associated with type 2 diabetes in rats and humans. The R1142C mutation specifically identified in Goto-Kakiza...

BACKGROUND Tks5 regulates invadopodium formation, but the precise timing during invadopodium lifetime (initiation, stabilization, maturation) when Tks5 plays a role is not known. RESULTS We report new findings based on high-resolution spatiotemporal live-cell imaging of invadopodium precursor assembly. Cortactin, N-WASP, cofilin, and actin arrive together to form the invadopodium precursor, f...