Boster Pathways-> Cellular Metabolism

Insulin Receptor signaling

Insulin signals control cell growth and metabolic homeostasis. Dysregulation of this pathway can lead to metabolic diseases, such as diabetes.

The Insulin Overview

Insulin is a peptide hormone mainly used to lower blood sugar levels. It is secreted by beta cells in the pancreatic islets in response to nutrient absorption and elevated blood sugar levels. When insulin binds to receptors on target cells (such as skeletal muscle cells and adipocytes), the signal cascade begins, and finally the glucose transporter GLUT4 is transferred from the intracellular vesicles to the cell membrane. Once GLUT4 binds to the plasma membrane, it promotes the uptake of extracellular glucose, and then stores it as glycogen in these cells, thereby regulating blood sugar.

Insulin also regulates blood sugar by inhibiting gluconeogenesis (de novo production of glucose) and glycogenolysis (glycogenolysis) in the liver. In addition to regulating blood sugar levels, insulin also plays a key role in promoting protein and lipid synthesis and preventing the conversion of proteins and fats into glucose.Although insulin is considered a hormone that regulates glucose homeostasis, more and more studies clarify the broader role of this peptide. The insulin signaling pathway is usually very conservative.

Insulin Receptor

The insulin receptor belongs to the superfamily of receptor tyrosine kinases (RTKs) and is activated by insulin and insulin-like growth factor (IGF12). It is a heterotetrameric protein consisting of two extracellular α subunits and two transmembrane β subunits, which are connected by disulfide bonds. Most RTKs bind directly to signal proteins. However, the insulin receptor binds to phosphorylated residues in associated proteins, a large family of docking proteins called the insulin receptor substrate family (IRS16), and the adapter protein Shc.

Insulin Protein Family

The insulin protein family combines several evolutionarily related active peptides: these include insulin, relaxin, insect pronuclides (bombyxin), insulin-like growth factors (IGF1 and IGF2), cell-specific insulin-like peptide mammalian Leydig ( INSL3 gene), early placental insulin-like peptide (ELIP), lobster insulin-related peptide (LIRP), mollusk insulin-related peptide (MIP) and Caenorhabditis elegans insulin-like peptide. The 3D structure of the different members of the family has been determined (Figure 3). The fold consists of two polypeptide chains (A and B) connected by two disulfide bonds: they all share the conservative arrangement of the four cysteines in the A chain, the first of which is connected to the third by a disulfide bond The second and the second and the fourth are connected to the cysteine ​​in the B chain through interchain disulfide bonds.

The insulin receptor pathway plays a key role in regulating metabolic homeostasis. Insulin receptors act as tyrosine kinases and, by binding to insulin, initiate a phosphorylation cascade, increasing the concentration of glucose transport molecules in muscle and adipose tissue. By combining with the AKT / PI3K pathway to maintain greater regulation, this also promotes the conversion of glucose into glycogen for cellular storage.

The Process Of Insulin Receptor Pathways

When insulin binds to the extracellular α subunit of the insulin receptor, it will cause a conformational change, which then leads to autophosphorylation of various tyrosine residues present on the β subunit. They form the binding site of the IRS protein, which contains the phosphotyrosine binding domain (PTB), or the Shc adaptor protein, which contains the srchomology 2 (SH2) domain. The combination of the insulin receptor and IRS or Shc forms a platform that allows the assembly of signal transduction particles, thereby generating multiple intracellular signaling pathways.

Insulin Receptor-mediated signal transduction can be divided into IRS-mediated signal transduction pathway and non-IRS-mediated signal transduction pathway according to whether it mediates IRS (insulin receptor substrate).

  • IRS-mediated insulin signaling pathway

    A series of IRS1~4 proteins are recruited and phosphorylated, of which IRS1 and IRS2 are the most widely expressed. Tyrosine phosphorylated IRS protein recruits and binds to signal molecules containing SH2 domains, which activate two signal transduction pathways in cells: 1) Phosphatidylinositol 3 kinase (PI3K) Protein kinase B (Akt or PKB) ) Pathway: the phosphorylated IRS protein then binds to the P85K subunit of PI3K and recruits its catalytic subunit P110 to activate PI3K; PI3K activates the phosphorylation of phosphatidylinositol to produce 3,4,5 phosphatidylinositol 3,4, 5 Triphosphate (PIP3), which in turn activates the serine/threonine protein kinase Akt, which activates a variety of substrates and mediates the action of insulin in a variety of organisms.

    Ras-mitogen-activated protein kinase(MAPK) pathway: the growth signaling pathway. Mammalian MAPK families include p38, extracellular-signal-regulated kinase(ERK) and c-Jun N-terminal kinase(JNK). IRS1/2 activates MAPK by binding to growth factor receptor-bound protein 2(Grb2), regulates gene transcription and regulates cell proliferation and differentiation by interacting with PI3K-AKT pathway.

  • Non-IRS-mediated insulin signaling pathway

    IRS1 to 4, several other substrates can also mediate the biological effects of insulin. 1) The homologous region of Src 2 contains protein. The activated insulin receptor phosphorylates the tyrosine residue Shc, which in turn binds to Grb2 to trigger the RasMAPK signaling pathway to regulate cell growth and proliferation. 2) Heterotrimeric G protein Gаq/11: Gaq/11 is phosphorylated by the active insulin receptor PI3K and stimulates GLUT4 to mediate glucose uptake. 3) Cbl-related protein (CAP): The protocarcinoma product Cbl adaptor protein is recruited to the insulin receptor near CAP, causing phosphorylation of the Cbl adaptor protein, and then the CAP/Cbl complex causes GLUT4 to be directly transported to the cell membrane and absorb glucose.

  • PI3K / AKT Pathway

    The regulatory effect of insulin on metabolism is mainly mediated by the PI3K (phosphoinositide 3-kinase) pathway. After IRS1 activates PI3K, activated PI3K catalyzes phosphorylation of phosphatidylinositol (PI) across the membrane to produce PIP2 (phosphatidylinositol 4,5 diphosphate) and PIP3 (phosphatidylinositol 3,4,5 triphosphate). PIP3 acts as a second messenger to recruit Akt and PDK1 (3-phosphoinositide-dependent protein kinase 1) to the envelope region (PTEN pathway), where phosphorylation of PDK1 activates the serine / threonine residues of Akt.

    Akt regulates the transport of the insulin-sensitive glucose transporter Glut4 in muscle and fat cells to the cell membrane to extract glucose. Akt also phosphorylates glycogen synthase kinase (GSK), inactivating the enzyme and inhibiting glycogen synthase (GS) activity. Gsk3 also inactivates the eukaryotic 2B promoter and promotes insulin-mediated protein synthesis.

  • Ras / MAPK Pathway

    The MAPK pathway is an important secondary branch of the insulin signaling pathway. It is activated by the binding of the growth factor receptor 2 (Grb2) binding protein to tyrosine phosphorylated Shc, or by the binding of Sh2 to the insulin receptor, independently of the PI3K pathway. The amino-terminal SH3 domain of Grb2 binds to proline-rich protein regions, such as Sonofsevenless (SOS), which is a guanine nucleotide exchange factor that catalyzes the conversion of membrane-bound Ras in an inactive form (RasGDP ) Active form (RasGTP).

    Activated RasGTP can then stimulate downstream effectors, such as serine / threonine kinase Raf, which activates its downstream targets MEK1 and MEK2, which in turn phosphorylates and activates extracellular signal-regulated MAP kinase 1/2 (ERK1 / 2 ). Activated ERK1 / 2s are directly involved in a variety of cellular processes, including cell proliferation and differentiation.

Regulation of IR Pathway

Since the insulin signaling pathway is a complex pathway, many factors can regulate this pathway. Studies have found that protein tyrosine phosphatase 1B (PTP1B) plays a role in regulating the sensitivity of insulin signaling pathways and energy metabolism. Importantly, PTP1B knockout mice are more sensitive to the insulin signaling pathway and are resistant to obesity. Specific PTP1B inhibitors can significantly increase the body's sensitivity to insulin; αG (α glucose): inhibiting the activity of α-glucoside can slow down the production and absorption of glucose. Improve pancreatic sensitivity, protect pancreatic function, effectively prevent diabetes and improve complications. The emergence of aldose reductase (AR) is a restriction enzyme of glucose metabolism. It catalyzes the conversion of glucose to sorbitol, weakens the appearance of the insulin signaling pathway, and ultimately triggers diabetes; dipeptide kinase IV (DPPIV) can cleave and inactivate intestinal stimuli Insulin weakens the sensitivity of the insulin signaling pathway. In addition, the NFκB signaling pathway is closely related to the development of insulin resistance. Abnormal expression of NFκB and its related genes can directly or indirectly affect the transmission of insulin signaling pathway in different parts of the body through different pathways.