Receptors that initiate signaling responses are generally integral membrane proteins present on the plasma membrane, where their extracellular domains recognize soluble secreted ligands or structures that are attached to the plasma membrane of a neighboring cell or cells. One distinct category of receptors, nuclear receptors, are actually transcription factors that are functionally activated by lipid-soluble ligands that can easily cross the plasma membrane.
The initiation of signaling from a cell surface receptor may require ligand-induced clustering of the receptor, known as receptor cross-linking, or may involve a conformational alteration of the receptor that is induced by its association with ligand. Both mechanisms of signal initiation typically result in the creation of a novel geometric shape in the cytosolic portion of the receptor that promotes interactions with other signaling molecules. This change in receptor geometry may sometimes result from enzymatic addition of a bulky phosphate residue on a key tyrosine, serine, or threonine side chain on the cytosolic portion of a receptor component or on a distinct adaptor protein. The enzymes that add phosphate groups onto amino acid side chains are called protein kinases. Many of the initiating events in lymphocyte signaling depend on protein kinases that phosphorylate key tyrosine residues, and these enzymes are therefore called protein tyrosine kinases. Other protein kinases that are involved in distinct signaling pathways are serine/ threonine kinases, enzymes that phosphorylate protein substrates on serine or threonine residues. Some enzymes activated downstream of signaling receptors phosphory-late lipid substrates; they are therefore known as lipid kinases. For every type of phosphorylation event, there is a specific phosphatase, an enzyme that can remove a phosphate residue and thus modulate signaling. These phosphatases play important, usually inhibitory roles in signal transduction. Phosphorylation of proteins is not the only post-translational modification that drives signal transduction. Many other modifications are known to facilitate signaling events. Some transcription factors as well as histones can be regulated by acetylation and methylation, for instance. A type of modification that we will describe later in this chapter is protein ubiq-uitination, the addition of ubiquitin molecules that either target proteins for degradation or drive signal transduction in many cells, including lymphocytes. Many important signaling molecules are modified by the addition of lipids that may help localize the protein in the plasma membrane, or sometimes to a specialized region of the plasma membrane that is rich in signaling molecules.
Non-receptor tyrosine kinase based receptor
Tyrosine kinase Ligand receptor
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