The intensity and duration of action of EGF, PDGF, and other agents that act via receptor tyrosine kinases are often limited by a process called receptor down-regulation. Ligand binding often induces accelerated endocytosis of receptors from the cell surface, followed by the degradation of those receptors (and their bound ligands). When this process occurs at a rate faster than de novo synthesis of receptors, the total number of cell-surface receptors is reduced (down-regulated), and the cell’s responsiveness to ligand is correspondingly diminished. A well-understood example is the EGF receptor tyrosine kinase, which internalizes from the plasma membrane at a greatly accelerated rate after activation by EGF and then is delivered to lysosomes and proteolyzed. This down-regulation process is essential physiologically to limit the strength and duration of the growth factor signal; genetic mutations that interfere with the down-regulation process cause excessive and prolonged responses that underlie or contribute to many forms of cancer. Endocytosis of other receptor tyrosine kinases, most notably receptors for nerve growth factor, serves a very different function. Internalized nerve growth factor receptors are not rapidly degraded but are translocated in endocytic vesicles from the distal axon, where receptors are activated by nerve growth factor released from the innervated tissue, to the cell body. In the cell body, the growth factor signal is transduced to transcription factors regulating the expression of genes controlling cell survival. This process, effectively opposite to down-regulation, transports a critical survival signal from its site of agonist release to the site of a critical downstream signaling effect and can do so over a remarkably long distance—up to a meter in some neurons.
A number of regulators of growth and differentiation, including TGF-β, act on another class of transmembrane receptor enzymes that phosphorylate serine and threonine residues. Atrial natriuretic peptide (ANP), an important regulator of blood volume and vascular tone, acts on a transmembrane receptor whose intracellular domain, a guanylyl cyclase, generates cGMP (see below). Receptors in both groups, like the receptor tyrosine kinases, are active in their dimeric forms.
Cytokine receptors respond to a heterogeneous group of peptide ligands, which include growth hormone, erythropoietin, several kinds of interferon, and other regulators of growth and differentiation. These receptors use a mechanism (Figure 2–8) closely resembling that of receptor tyrosine kinases, except that in this case, the protein tyrosine kinase activity is not intrinsic to the receptor molecule. Instead, a separate protein tyrosine kinase, from the Janus-kinase (JAK) family, binds noncovalently to the receptor. As in the case of the EGF receptor, cytokine receptors
FIGURE 2–8 Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate transcription.
dimerize after they bind the activating ligand, allowing the bound JAKs to become activated and to phosphorylate tyrosine residues on the receptor. Phosphorylated tyrosine residues on the receptor’s cytoplasmic surface then set in motion a complex signaling dance by binding another set of proteins, called STATs (signal transducers and activators of transcription). The bound STATs are themselves phosphorylated by the JAKs, two STAT molecules dimerize (attaching to one another’s tyrosine phosphates), and finally the STAT/STAT dimer dissociates from the receptor and travels to the nucleus, where it regulates transcription of specific genes.