Schematic diagram of downstream signaling pathways mediated by Insulin receptor. Credit: Tatulian, 2015
Insulin receptor (IR) is a member of receptor tyrosine kinases having the critical role in the insulin-mediated regulation of central metabolism, growth, and development. It is a tetramer of (αβ)2 type tyrosine kinase. Each αβ heterodimer is composed of an extracellular ligand binding α subunit and transmembrane-spanning β subunits which are linked by a disulfide linkage; however, these subunits assembled into tetramer (αβ)2 by 2 to 4 disulfide bonds between the α subunits.
When insulin binds to the α-subunits, it induces the conformational changes that lead to the trans-autophosphorylation of tyrosine residues located in the β-subunits (autophosphorylation of β-subunit by one another) thereby activating the downstream signaling cascade. The activated (autophosphorylated) tyrosine residues in the β-subunits of the IR initiate the downstream signaling cascade by phosphorylating the tyrosine residues of the downstream signaling proteins.
The main downstream signaling pathway mediated by IR signaling is the Akt2-mediated signaling pathway that is responsible for the translocation of the glucose transporter (Glut4) into the plasma membrane. This translocation is necessary for the intake of glucose, glycogen synthesis, synthesis of proteins and triglycerides as well as mitogen-activated protein kinase (MAPK) mediated regulation of gene expressions.
According to studies, about 5 % of the type-2 diabetes cases result from the mutations and destabilization of the tyrosine kinase domain of the insulin receptor leading to the molecular dysfunction. In addition to that, mutation of cysteine residues to serine in the α-subunits prevents the covalent linkage of α-subunits thereby destabilized the βα-αβ structure. Insulin binding to the C-terminal of the α-subunits is an induced fit mechanism in which insulin interacts with the IR in such a way that those two α-subunits antiparallelly interact with each other.
Insulin receptor follows the two main downstream signaling pathways which are Akt2 signaling pathway and MAPK signaling pathway. Activated tyrosine kinase domain of the IR activates the downstream insulin receptor substrate (IRS) signaling proteins that can either follow the Akt2 pathway or MAPK pathway depending upon the current need of the system.
In Akt2 signaling pathway, activated IRS protein activates the phosphatidylinositol-3-kinase (PI-3K) by phosphorylating its regulatory domain. Activated PI-3K leads to the phosphorylation of the phosphatidylinositol-4, 5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 then recruits the pleckstrin homology domain containing enzymes such as PDK1 and Akt2. PDK1 phosphorylates the PIP3 bound Akt2 and mediates the translocation of Glut4 into the plasma membrane thereby allowing the glucose influx. In addition to the translocation of the Glut4, Akt2 also mediates the glycogen synthesis by activating the glycogen synthase kinase-3 (GSK3).
While in MAPK signaling pathway, phosphorylated and activated IRS-1 activates the SH2 domain of the Grb2 protein that leads to the phosphorylation and activation of the downstream signaling proteins; Sos and Rap thereby activating the MAPK pathway. MAPK pathway involves the nuclear translocation and regulation of different transcription factors and thus modulates the gene expression responsible for the cell proliferation and differentiation.
Reference: Structural Dynamics of Insulin Receptor and Transmembrane Signaling
Article doi: 10.1021/acs.biochem.5b00805