Question

Describe how a single protein in the tyrosine kinase signaling pathway possesses all the protein functions that characterize signal transduction.

Answer 1

Receptor tyrosine kinases, which phosphorylate specific tyrosine residues on a small set of intracellular signaling proteins. EGF is a small protein (53 amino acids) that stimulates the proliferation of epidermal cells and a variety of other cell types. Its receptor is a single-pass transmembrane protein of about 1200 amino acids, with a large glycosylated extracellular portion that binds EGF. An intracellular tyrosine kinase domain is activated when EGF binds to the receptor. Once activated, the receptors transfer a phosphate group from ATP to selected tyrosine side chains, both on the receptor proteins themselves and on specific cellular proteins.

It was found that the ligand binding causes the EGF receptor to assemble into dimers, which enables the two cytoplasmic domains to cross-phosphorylate each other on multiple tyrosine residues. This cross-phosphorylation is referred to as autophosphorylation because it occurs within the receptor dimer.In the case of PDGF receptors the ligand is a dimer that cross-links two receptors together,EGF by contrast, is a monomer that is thought to induce a conformational change in the extracellular domain of its receptors to induce receptor dimerization. It is thought that receptor dimerization is a general mechanism for activating enzyme-linked receptors with a single transmembrane domain.

The autophosphorylated tyrosines serve as high-affinity binding sites for a number of intracellular signaling proteins in the target cell. Each of these proteins binds to a different phosphorylated site on the activated receptor, recognizing surrounding features of the polypeptide chain in addition to the phosphotyrosine. Once bound, many of these proteins become phosphorylated themselves on tyrosines and are thereby activated. In this way tyrosine autophosphorylation is thought to serve as a switch to trigger the transient assembly of an intracellular signaling complex, which serves to relay the signal into the cell interior. Different receptor tyrosine kinases bind different combinations of these signaling proteins and therefore activate different responses.