Related Experiment Video
Updated: Jun 5, 2026
08:45
Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
The lipid phosphatase SHIP2 controls insulin sensitivity
S Clément1, U Krause, F Desmedt
1IRIBHN, IBMM, rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium.
Nature
|May 9, 2001
Summary
SHIP2 negatively regulates insulin signaling. Mice lacking SHIP2 exhibit severe hypoglycemia and perinatal death, while heterozygous mice show enhanced insulin sensitivity and glucose tolerance.
Area of Science:
- Biochemistry
- Endocrinology
- Molecular Biology
Background:
- Insulin is crucial for glucose homeostasis; its impaired action or secretion contributes to diabetes mellitus.
- Type-II SH2-domain-containing inositol 5-phosphatase (SHIP2) is implicated in growth factor and insulin signaling pathways.
- SHIP2 interacts with phosphoinositide-3-OH kinase and Ras/mitogen-activated protein kinase pathways.
Purpose of the Study:
- To investigate the in vivo role of SHIP2 in insulin signaling and glucose homeostasis.
- To characterize the physiological consequences of SHIP2 gene deletion.
Main Methods:
- Generation and analysis of mice lacking the SHIP2 gene.
- Assessment of insulin sensitivity, glucose tolerance, and gene expression.
- Evaluation of GLUT4 transporter recruitment and glycogen synthesis.
Main Results:
- Complete loss of SHIP2 resulted in severe neonatal hypoglycemia, deregulated gluconeogenesis gene expression, and perinatal lethality.
- Heterozygous SHIP2-mutant adult mice displayed improved glucose tolerance and insulin sensitivity.
- Enhanced insulin sensitivity in heterozygotes was linked to increased GLUT4 transporter recruitment and glycogen synthesis in skeletal muscles.
Conclusions:
- SHIP2 acts as a potent negative regulator of insulin signaling and insulin sensitivity in vivo.
- Modulating SHIP2 activity could be a therapeutic strategy for metabolic disorders like diabetes.
More Related Videos
Related Concept Videos
02:54Protein Kinases and Phosphatases
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
01:42Phosphoinositides and PIPs
Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
01:05Insulin Secretory Vesicles
Insulin secretory vesicles release insulin to stimulate blood glucose uptake and regulate carbohydrate metabolism. When the blood glucose levels increase, glucose enters the pancreatic β-islet cells through glucose transporters. Once inside, glucose is metabolized through glycolysis, the citric acid cycle, and the electron transport chain, producing ATP. This increase in ATP concentration closes ATP-sensitive potassium channels, leading to depolarization of the membrane and the opening of...
01:20The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
01:22PI3K/mTOR/AKT Signaling Pathway
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a rapamycin-insensitive companion...
01:28Insulin: The Receptor and Signaling Pathways
Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but this inhibition is released...