Insulin signaling plays a crucial role as a growth factor in cellular processes. The peptide hormone insulin, composed of 51 amino acids, acts as a ligand that binds to the insulin receptor, which is classified as a receptor tyrosine kinase (RTK). This binding triggers autophosphorylation of the insulin receptor, fully activating it to phosphorylate its substrate, insulin receptor substrate 1 (IRS-1). The phosphorylation occurs specifically on tyrosine residues, facilitated by the tyrosine kinase domains of the receptor.
Once activated, IRS-1 serves as a docking site for the adapter protein Grb2, which binds to IRS-1 through its SH2 domain. Subsequently, the SH3 domain of Grb2 interacts with the guanine exchange factor (GEF) called SOS. This interaction promotes the exchange of GDP for GTP on the small GTPase RAS, activating it. Activated RAS then stimulates the MAP kinase cascade by activating RAF-1, which in turn activates MEK, another MAP kinase kinase (MAPKK). MEK phosphorylates and activates ERK, a mitogen-activated protein kinase (MAPK), which translocates to the nucleus to regulate transcription factors involved in cell growth.
Termination of the insulin signaling pathway is equally important. This is achieved through the action of phosphatases that remove phosphate groups, as indicated by the red arrows in the signaling diagram. Additionally, RAS inactivation is facilitated by GTP hydrolysis, a process that is slow and requires the assistance of GTPase-activating proteins (GAPs) to accelerate the signal termination.
To aid in memorization of the insulin signaling components, a mnemonic story can be helpful. It begins with the activation of IRS-1, likened to receiving a tax refund, which allows the cell to order food (Grubhub). Upon the food's arrival, hot sauce is added, symbolizing the activation of RAS. The cell then consults "Doctor Raph," who alleviates the "irking pain," representing the downstream effects of the signaling pathway.
This overview encapsulates the essential elements of insulin signaling as a growth factor, highlighting the intricate interactions and regulatory mechanisms that govern cellular growth and function.
