In general, there are five basic types of receptors. They include 1. a lipid -solube ligand that crosses the membrane and acts on an intracellular receptor (see detail here at http://www.tomhsiung.com/wordpress/2014/10/intracellular-receptors-for-lipid-soluble-agents/); 2. a transmembrane receptor protein whose intracellular enzymatic activity is allosterically regulated by a ligand that binds to a site on the protein’s extracellular domain; 3. a transmembrane receptor that binds and stimulates a protein tyrosine kinase; 4. a ligand-gated transmembrane ion channel that can be induced to open or closed by the binding of a ligand; and 5. a transmembrane receptor protein that stimulates a GTP-binding signal transducer protein (G protein, see the post of http://www.tomhsiung.com/wordpress/2014/09/g-protein-coupled-receptors/), which in turn modulates production of an intracellular second messenger.
Type 2 and type 3 receptors belong to transmembrane enzymes including receptors.
Transmembrane enzymes including receptors contain two types of receptors. One is called enzymes including receptors tyrosine kinases, the other is called cytokinesis receptors. Neoplastic disorders are often correlate with enhanced effects and activities of tyrosine kinases receptors since in these diseases excessive growth factor signaling is often involved (see below).
Enzymes Including Receptor Tyrosine Kinases
The class of transmembrane tyrosine kinases receptor molecules mediates the first steps in signaling by insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), atrial natriuretic peptide (ANP), and many other trophic hormones. These receptors are polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain (effector element), which may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase. In all these receptors, the two domains are connected by a hydrophobic segment of the polypeptide that crosses the lipid bilayer of the plasma membrane.
The receptor tyrosine kinase signaling pathway begins with binding of ligand, typically a polypeptide hormone or growth factor, to the receptors’ extracellular domain. This results in receptor conformation change that causes two receptor molecules to bind to one another (we call this phenomenon “dimerize”), which in turn brings together the tyrosine kinase domain. And subsequently the tyrosine kinases of the two receptor molecules become enzymatically active, thereafter they phosphorylate one another as well as additional downstream signaling proteins.
The function of the tyrosine kinase connected with the transmembrane receptor is to catalyze phosphorylation of tyrosine residues on different target signaling proteins (the downstream sinaling proteins just mentioned above), thereby allowing a single type of activated receptor (conformation change induced by the ligand) to modulate a number of biochemical processes. Some receptor tyosine kinases form oligomeric complexes larger than dimers upon activation by ligand, but the pharmacological significance of such higher-order complexes is presently unclear.
Regulation of Tyrosine Kinase Receptors
The intensity and duration of action of action of ligands of tyrosine kinase receptors that act via receptor tyrosine kinases are 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-regulation), and the cell’s responsiveness to ligand is correspondingly diminished.
A well-understood example is the EGF receptor tyrosine kinase, which undergoes rapid endocytosis followed by proteolysis in lysosomes after EGF binding; genetic mutations that interfere with this process cause excessive growth factor-induced cell proliferation and are associated with an increased susceptibility to certain types of cancer.
Endocytosis of other receptor tyrosine kinases, most notably receptors for nerve growth factor, serves a very different function. Internalised nerve growth factor receptors are not rapidly degraded and 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 traduced to transcription factors regulating the expression of genes controlling cell survival. This process effectively transports a critical survival signal from its site of release to its site of signalling effect, and does so over a remarkably long distance – up to 1 meter in certain sensory neurons.
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 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.
Cytokines first activate the cytosine receptors, then the JAK involved with the cytokine receptors are activated, resulting in phosphorylation of signal transducers and the resultant activation of transcription molecules like STAT. STAT dimers then travel to the nucleus, where they regulate transcription.