Fig. 1.12 Receptor-mediated signaling. (A) Categories of signaling receptors, including receptors that use a nonreceptor tyrosine kinase; a receptor tyrosine kinase; a nuclear receptor that binds its ligand and can then influence transcription; a seven-transmembrane receptor linked to heterotrimeric G proteins; Notch, which recognizes a ligand on a distinct cell and is cleaved yielding an intracellular fragment that can enter the nucleus and influence transcription of specific target genes; and the Wnt/Frizzled pathway where activation releases intracellular β-catenin from a protein complex that normally drives its constitutive degradation. The released β-catenin can then migrate to the nucleus and act as a transcription factor. Lrp5/Lrp6, low-density lipoprotein (LDL) receptor-related proteins 5 and 6, are highly homologous and act as coreceptors in Wnt/Frizzled signaling. (B) Signaling from a tyrosine kinase-based receptor. Binding of the growth factor (ligand) causes receptor dimerization and autophosphorylation of tyrosine residues. Attachment of adapter (or bridging) proteins couples the receptor to inactive, GDP-bound RAS, allowing the GDP to be displaced in favor of GTP and yielding activated RAS. Activated RAS interacts with and activates RAF (also known as MAP kinase kinase kinase). This kinase then phosphorylates mitogen-activated protein kinase (MAPK), and activated MAP kinase phosphorylates other cytoplasmic proteins and nuclear transcription factors, generating cellular responses. Activated RAS can also interact with other components, such as phosphatidyl 3-kinase (PI3 kinase), which activates other signaling systems. The cascade is turned off when the activated RAS eventually hydrolyzes GTP to GDP converting RAS to its inactive form. Mutations in RAS that lead to delayed GTP hydrolysis can thus lead to augmented proliferative signaling. GDP, Guanosine diphosphate; GTP, guanosine triphosphate; mTOR, mammalian target of rapamycin.
Fig. 1.12 ). The common theme is that all of these perturbations cause a change in the physical state of the intracellular domain of the receptor, which then triggers additional biochemical events that lead to signal transduction.
Cellular receptors are grouped into several types based on the signaling mechanisms they use and the intracellular biochemical pathways they activate (
Fig. 1.12 ). Receptor signaling most commonly leads to the formation or modification of biochemical intermediates and/or activation of enzymes, and ultimately to the generation of active transcription factors that enter the nucleus and alter gene expression: