Signal transduction

Definition

Signal transduction is the mechanism by which cells respond to external signals such as hormones or peptides. The process begins with a ligand binding to a cell-surface receptor, which initiates a cascade of intracellular molecular events that ultimately produce a cellular response. The cascade typically involves activation of intracellular proteins such as G-proteins, tyrosine kinases, or serine/threonine kinases; generation of second messengers such as cAMP or calcium ions; and activation of transcription factors that alter gene expression. Different receptors activate different signal-transduction pathways; the same cell may respond to the same signal through multiple pathways depending on the receptor and context. In research, understanding the signal-transduction pathway activated by a peptide compound helps explain its biological effects and can reveal unintended off-target signaling. Dysregulation of signal-transduction pathways contributes to diseases including cancer, metabolic disorders, and neurological disorders.

G-protein-coupled receptors (GPCRs), a large family that includes GLP-1 receptors and other peptide hormone receptors, activate heterotrimeric G-proteins (Gs, Gi/o, Gq, G12/13) upon ligand binding. Activation of Gs-coupled receptors increases intracellular cAMP, a second messenger that activates protein kinase A (PKA) and leads to phosphorylation of downstream targets and altered gene expression. Activation of Gq-coupled receptors increases intracellular calcium, activating calcium-dependent enzymes. These different signaling pathways produce different cellular responses, allowing the same hormone to produce diverse effects depending on which receptors are activated in which tissues.

Receptor tyrosine kinases (RTKs) activate different pathways, involving phosphorylation of the receptor itself and recruitment of adaptor proteins that activate kinase cascades such as the MAPK/ERK pathway or the PI3K/Akt pathway. These pathways regulate cell growth, proliferation, and survival. Dysregulation of RTK signaling is a hallmark of cancer. Research into peptide signaling has revealed that many peptides activate multiple signaling pathways simultaneously, and the relative contribution of each pathway to the overall biological effect is an active area of investigation.