Cytokines, Growth Factors and Hormones Cytokines, growth factors (GF), and hormones are all chemical messengers that mediate intercellular communication. The regulation of cellular and nuclear functions by cytokines, growth factors, and peptide or protein hormones is initiated through the activation of cell surface receptors (Rc). All receptors have two main components: 1) a ligand-binding domain that ensures ligand specificity and 2) an effector domain that initiates the generation of the biological response upon ligand binding. The activated receptor may then interact with other cellular components to complete the signal transduction process. Many growth factors bind to receptors that are linked through G-proteins to membrane-bound phospholipase C (PLC). Activation of PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) to form diacylglycerols (DAG) and D-myo-inositol-1,4,5-triphosphate (IP3). IP3 regulates intracellular Ca2+by binding to the IP3 receptor on the endoplasmic reticulum (ER) and stimulating Ca2+ release from the ER. Free intracellular Ca2+ can bind to calmodulin, and this Ca2+-calmodulin complex, in the presence of cyclic-AMP (cAMP), activates protein kinase A (PKA) by binding to the regulatory subunit of the enzyme. DAG binds to and activates protein kinase C (PKC). Other hormone receptors may be linked through G-proteins to adenylate cyclase (AC) instead of PLC. Activation of AC increases the cellular levels of cAMP and, in the presence of the Ca2+-calmodulin complex, will activate PKA. Additionally, some growth factor and cytokine receptors are protein tyrosine kinases (PTK) that are directly activated by ligand-receptor interaction. Activation of any of the protein kinases, PKA, PKC, or PTK, catalyzes the phosphorylation of other proteins within the cell. Enzymes that are activated or inhibited by phosphorylation may mediate functional processes within the cell, while others may be one step in a protein kinase cascade that regulates nuclear events. Steroid hormones (i.e. estrogen, glucocorticoids), thyroid hormone, vitamin D3, and retinoids are all small lipophilic molecules that easily penetrate both the cellular and nuclear membranes to enter the nucleus where they bind to their respective receptors that are ligand-dependent transcription factors. These ligand-receptor complexes bind to specific DNA response elements in the promoter region and regulate gene expression. References: Luttrell, L.M., et al., G-protein-coupled receptors and their regulation: activation of the MAP kinase signaling pathway by G-protein-coupled receptors. Adv. Second Messenger Phosphoprotein Res., 31, 263-277 (1997). Marshall, C.J., Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell, 80, 179-185 (1995). Kumar, R., and Thompson, E.B., The structure of the nuclear hormone receptors. Steroids, 64, 310-319 (1999).