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The receipt of informational signals by a cell is a complex task. For this purpose, cells display an extraordinarily elaborate array of transmembrane proteins termed receptors that function to acquire information from the extracellular space and relay this information into the cell through the plasma membrane . In effect, cell surface receptors act as the antennae of the cell.

Mammalian cells like our own have wide and diverse types of transmembrane receptors, but we will focus only on a subset of them, specifically:

Growth Factor Receptors

One class of well-studied receptors is involved in helping the cell determine whether or not it should grow. As we will discuss shortly in connection with the cell cycle , a cell determines whether or not it should grow from growth factors that may be present in the medium around it. These growth factors, sometimes termed mitogens because they induce the cell to grow and pass through mitosis, are themselves polypeptides , often 50-100 amino acids long. When present in sufficient quantity, a growth factor (GF) will stimulate a cell to enter into a round of growth and division.

GFs act by binding to cell surface GF receptors. Each type of GF binds to the extracellular domain of its own specific receptor and conversely will not bind to receptors for other growth factors. This extracellular receptor domain can be viewed as having a pocket that specifically accommodates the appropriate growth factor in a lock-and-key fashion and at the same time excludes all others. Thus, epidermal growth factor (EGF) will only bind to the EGF receptor on the surface of cells but not to the PDGF (platelet-derived growth factor) receptor that may also be displayed on the cell surface.

In general, each type of receptor is said to bind specifically to its own ligand . Other ligands besides growth factors may convey signals from cell to cell through intercellular space. There are at least several hundred distinct receptor: ligand pairs in our body, each devoted to the binding of a distinct extracellular ligand such as a growth factor to its cognate receptor. Each ligand originates elsewhere in the tissue or organism, being secreted by a cell or cells specialized for its release.

Transmembrane signal transduction

The binding of a growth factor to the extracellular domain of its cognate receptor is only the beginning of the signalling process. How is the news of this encounter conveyed across the plasma membrane into the cell? Such transmission of information by a protein is often termed by biochemists as a form of signal transduction. The answer comes from examining the detailed structures of many GF factor receptor proteins. Outside the cell, they have a ligand-binding N- terminal ectodomain, followed by a single membrane-spanning transmembrane domain. At their C-termini in the cytoplasm, they have a specialized enzyme domain that becomes activated whenever the extracellular domain of the receptor encounters and binds a GF ligand. In the case of many GF receptors, this cytoplasmic enzyme domain contains protein kinase activity.

Recall that kinases are enzymes that attach phosphate groups to their substrates. Protein kinases take the gamma-phosphates from ATP and transfer them to protein substrates, resulting in the phosphorylation of the substrate proteins. In the case of GF receptors, the phosphate groups are attached to the tyrosine side chains of substrate proteins that communicate with or lie near the cytoplasmic domains of the GF receptors. Accordingly, these receptors are considered to have protein tyrosine kinase activity to distinguish them from many other protein kinases throughout the cell that are devoted to other signalling functions and attach phosphates to serine or threonine side chains of their substrates.

The sequence of events is then as follows:

  1. The GF ligand binds to the extracellular domain of its receptor.
  2. This results in the activation of the tyrosine kinase domain at the other end of the receptor that is present in the cytoplasm.
  3. The tyrosine kinase becomes active and phosphorylates a series of cytoplasmic substrate proteins that in turn become activated or altered functionally as a consequence of having become phosphorylated.
  4. They then proceed to send signals further into the cell in a manner that ultimately results in the cell growing and dividing.
Note that the GF ligand itself does not need to become internalized (physically transported) into the cell in order for this transmembrane signalling to occur. All active transmembrane signal transduction occurs while the ligand is still in the extracellular space. None of this tells us precisely how the association of the GF ligand outside the cell causes tyrosine kinase activation inside the cell. A number of mechanisms could be envisaged to make this possible. The one that is often used depends on two important biochemical facts. First, there are many copies of each type of GF receptor molecule that are displayed on the surface of a given cell. Second these receptor molecules, while tethered in the plasma membrane via their hydrophobic transmembrane domains, are to diffuse laterally through the plane of the plasma membrane.

When a GF ligand binds to a single receptor molecule,this encourages the dimerization of the receptor with another one floating nearby in the plasma membrane. Often the GF ligand itself has two receptor-binding ends, enabling it to serve as a bridge between the two receptors that attracts two receptors, encourages their dimerization, and stabilizes the resulting receptor dimer pair. The dimerization of the extracellular domain in turn drags the cytoplasmic domains of the two receptors molecules into close juxtaposition. The tyrosine kinase (TK) of one receptor molecule then phosphorylates the kinase domain of the second receptor molecule with which it has come in close contact following ligand binding. This phosphorylation results in a steric shift in the 3-dimensional structure of the phosphorylated kinase domain and in turn causes its functional activation. In effect, the two kinase domains, once they are brought face-to-face, phosphorylate and thereby activate each other. Once they are activated, they then proceed to phosphorylate a multitude of nearby cytoplasmic substrate proteins that then pass signals further into the cell.

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