Enzyme-Linked Receptors

• Receptor tyrosine kinases (RTK) are receptor kinases that phosphorylate (add phosphate groups) to tyrosine residues on intracellular signaling proteins. There are seven subtypes of RTK with varying extracellular domains.

• Receptor serine-threonine kinases are receptor kinases that phosphorylate serine and/or threonine residues on associated latent gene regulatory proteins.

• Receptor guanylyl cyclases generate second messenger cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP) in the cytosol.

• Histidine-kinase-associated receptors initiate a "two-component" signaling pathway in which the kinase phosphorylates itself on histidine and then passes the phosphate to a second intracellular signaling protein.

Another type is the receptor-like tyrosine phosphatases that remove phosphate groups from tyrosine in specific intracellular signaling proteins. They are considered “receptor-like” because their corresponding ligands have not yet been identified, meaning their function as receptors has not been explicitly demonstrated.

Mechanism for activation of enzyme-linked receptors

For most enzyme-linked receptors, ligand binding induces their dimerization or, in some cases, oligomerization. This causes cytoplasmic enzymatic domains to combine, resulting in a change in enzymatic activity, which is essentially their activation.

Dimerization can occur between separate receptors that bind the same ligand (heterodimerization) or between receptor chains of the same type (homodimerization).

RTKs, RTPs, and guanylyl cyclase receptors often form homodimers (the epidermal growth factor (EGF) receptor tyrosine kinase being an exception), whereas receptor serine–threonine kinases typically form heterodimers. While this is generally the case, there are times when activation requires the oligomerization of several receptors.

How enzyme-linked receptors activate signaling pathways

Now that we have discussed the definition and types of enzyme-linked receptors, here we will discuss specific examples--receptor tyrosine kinase and insulin--and how they activate signaling pathways.

Receptor Tyrosine Kinase

There are more than 16 structural subfamilies of receptor tyrosine kinases, each with its own family of protein ligands.

Extracellular signal proteins that operate via receptor tyrosine kinases include a wide range of secreted growth factors and hormones including insulin (which we will discuss further later).

When a ligand binds to the ligand-binding domain on the cell's surface, it activates the intracellular tyrosine kinase domain. Upon activation, the kinase domain moves a phosphate group from ATP to specific tyrosine side chains on receptor proteins as well as intracellular signaling proteins that interact with the phosphorylated receptors.

The rearrangement in receptor tyrosine kinases allows adjacent kinase domains of the receptor chains to cross-phosphorylate each other on numerous tyrosines, a process known as autophosphorylation.

Autophosphorylation of receptor tyrosine kinase cytosolic tails results in activation in two ways:

1. The phosphorylation of tyrosines inside the kinase domain boosts the enzyme's kinase activity.

2. The phosphorylation of tyrosines outside the kinase domain generates high-affinity docking sites in the target cell for the binding of various intracellular signaling proteins.

Once attached to the active kinase, the signaling protein may get phosphorylated on tyrosines and therefore activated. On the other hand, it could also be the case that binding alone suffices to activate the docked signaling protein.

Autophosphorylation acts as a switch to activate the transitory formation of a large intracellular signaling complex, which subsequently transmits signals to many parts of the cell. Different receptor tyrosine kinases bind different combinations of these signaling proteins, which in turn triggers varying reactions.

The binding of intracellular signaling proteins to a tyrosine kinase receptor that has been activated creates a signaling complex that can subsequently send signals along various signaling pathways. Some docked proteins are enzymes that activate the inositol phospholipid signaling pathway by which receptor tyrosine kinases can enhance cytosolic Ca2+ levels. Typically such receptors rely on relay chains of protein-protein interactions.

Figure 2. This diagram summarizes how RTK is activated, triggering a cascade of signals, and ultimately triggering a response.

Enzyme-linked receptors insulin

Insulin is a hormone secreted by pancreatic b cells that acts through a receptor located in the membrane of target cells, the most important of which are:

• The liver: where it promotes glucose storage into glycogen and decreases glucose output

• Skeletal muscle and fat: where it stimulates glucose transport through GLUT4 translocation

• B cells, brain cells, and many other types of cells: where it produces numerous and varying impacts

The insulin receptor is a member of the tyrosine kinase receptor superfamily. We have discussed the mechanism by which RTK activates signaling pathways, but insulin receptors are a bit different.

The insulin receptors are tetramers (composed of four identical building blocks) to begin with, and its interaction with a ligand is thought to result in the rearrangement of transmembrane receptor chains such that the two kinase domains are brought together. The majority of the phosphotyrosine docking sites formed by ligand interaction are found on a specific docking protein termed insulin receptor substrate-1 (IRS-1) rather than on the receptor itself.

The active receptor autophosphorylates its kinase domains, which subsequently phosphorylate IRS-1 on many tyrosines, resulting in more docking sites than the receptor alone could accommodate. Some receptor tyrosine kinases employ other docking proteins in a similar manner to increase the size of the signaling complex.