Receptors associated with kinase activity. Downstream phosphorylation is a common pathway of signal transduction. Changes in receptor geometry can stimulate intrinsic receptor protein kinase activity or promote the enzymatic activity of recruited intracellular kinases. These kinases add charged phosphate residues to target molecules. Tyrosine kinases phosphorylate specific tyrosine residues, whereas serine/threonine kinases add phosphates to distinct serine or threonine residues, and lipid kinases phosphorylate lipid substrates. For every phosphorylation event, there is also a potential counter-regulatory phosphatase, an enzyme that can remove the phosphate residue and thus modulate signaling; usually, phosphatases play an inhibitory role in signal transduction.
Receptor tyrosine kinases (RTKs) are integral membrane proteins (e.g., receptors for insulin, epidermal growth factor, and platelet-derived growth factor [PDGF]); ligand-induced crosslinking activates intrinsic tyrosine kinase domains located in their cytoplasmic tails.
Several kinds of receptors have no intrinsic catalytic activity (e.g., immune receptors, some cytokine receptors, and integrins). For these, a separate intracellular protein—known as a nonreceptor tyrosine kinase— interacts with receptors after ligand binding and phosphorylates specific motifs on the receptor or other proteins. The cellular homolog of the transforming protein of the Rous sarcoma virus, called SRC, is the prototype for an important family of such nonreceptor tyrosine kinases (Src-family kinases). SRC contains unique functional regions called Src-homology (SH) domains; SH2 domains typically bind to receptors phosphorylated by another kinase, allowing the aggregation of multiple enzymes, whereas SH3 domains mediate protein–protein interactions, often involving proline-rich domains.
G-protein coupled receptors are polypeptides that characteristically traverse the plasma membrane seven times (hence their designation as seven-transmembrane or serpentine receptors); more than 1500 such receptors have been identified. After ligand binding, the receptor associates with an intracellular guanosine triphosphate (GTP)-binding protein (G protein). At baseline, these G proteins contain guanosine diphosphate (GDP); interaction with a receptor-ligand complex results in G protein activation through the exchange of GDP for GTP. Downstream signaling typically involves the generation of cAMP, and inositol-1,4,5,-triphosphate (IP3), the latter releasing calcium from the ER.
Nuclear receptors. Lipid-soluble ligands can diffuse into cells where they interact with intracellular proteins to form a receptor-ligand complex that directly binds to nuclear DNA; the results can be either activation or repression of gene transcription.
Other classes of receptors. Other receptors—originally recognized as important for embryonic development and cell fate determination—have since been shown to participate in the functions of mature cells, particularly within the immune system. These pathways rely on protein:protein interactions, rather than enzymatic activities, to transduce signals, which may serve to allow for very precise control.
Receptor proteins of the Notch family: ligand binding to Notch receptors leads to proteolytic cleavage of the receptor and subsequent nuclear translocation of the cytoplasmic domain (intracellular Notch) to form a transcription complex.
Wnt protein ligands act through a pathway involving transmembrane Frizzled family receptors, which regulate the intracellular levels of β-catenin. In the absence of Wnt, β-catenin is targeted for ubiquitindirected proteasome degradation. Wnt binding to Frizzled (and other coreceptors) recruits other proteins that disrupt the degradation-targeting complex. This stabilizes β-catenin, allowing it to translocate to the nucleus and form a transcription complex.
ModularSignalingProteins,Hubs,andNodes