Signal Transduction

How does the cell "know" when a particular receptor molecule in the membrane is occupied, and how is that information chemically translated into actions within the cell? Let us examine the signaling pathway for the receptor tyrosine kinases (RTK). The RTKs are a very powerful and important family of signaling molecules and include receptors for potent growth factors and such hormones as insulin, epidermal growth factor, and nerve growth factor.

In this system, the extracellular "ligand" (growth factor or hormone) must crosslink two receptor molecules in order to begin the transduction cascade. The interaction of the two intracellular domains of the receptors then initiates a signaling response.

The simplest RTKs have three parts: a ligand binding site outside the cell, a single membrane-spanning domain, and a tyrosine kinase domain inside the cell. The ligand is typically a diffusible peptide or small protein In the GPCR pathway, an external signal causes an internal, multi-part G protein to exchange GDP for GTP. It then activates adenyl cyclase and ultimately triggers gene transcription. produced elsewhere in the organism, and in this case is the specific growth factor recognized by the RTK. In the absence of its specific growth factor, this receptor remains unbound to a second receptor, and is inactive. Growth factor, when it arrives, binds to two receptors, cross-linking them. This causes the two tyrosine kinase domains to come into contact with one another. Each kinase now has a substrate, formed by the other receptor, and so each phosphorylates the other on multiple tyrosine sites.

The receptors may now bind with one or more other proteins (called SH2 proteins) that specifically recognize their phosphorylated tyrosines. Many of these are enzymes, while others are adapter molecules that in turn attract and bind other enzymes. Often these enzymes are inactive until they join the receptor complex, because their substrates are found only in the membrane. The products of these enzymes may act on yet other molecules, thus continuing the signaling cascade, or they may be used in cell metabolism for growth or other responses.