Signal Initiation and Receptor Complex Assembly
Signal transduction begins at the plasma membrane. Initiators include various growth factors, such as epidermal growth factor (EGF) or nerve growth factor (NGF).
- Ligand binding and receptor activation. A growth factor binds to its specific receptor (a receptor tyrosine kinase). This induces receptor dimerization—the association of two receptor subunits. Immediately following, transautophosphorylation occurs: the receptor attaches phosphate groups to tyrosine residues on its own cytosolic (intracellular) domain.
- Recruitment of adapter proteins. Phosphorylation dramatically alters the spatial conformation of the receptor, significantly increasing its affinity for the membrane adapter protein Grb2.
- Interaction with the exchange factor. The binding of Grb2 to the receptor creates conditions for the recruitment of the cytosolic protein SOS, which functions as a guanine nucleotide exchange factor (GEF). As a result, a multi-component complex forms on the inner surface of the membrane.
Ras Activation and Initiation of the Kinase Cascade
The central link transmitting the signal from the receptor complex to the cytosol is the small G-protein Ras. In its inactive state, it is bound to a guanosine diphosphate (GDP) molecule and firmly anchored to the cell membrane.
- Nucleotide exchange. The SOS protein within the receptor complex increases affinity for Ras and induces a conformational change. Consequently, the affinity of Ras for GDP drops sharply, GDP dissociates, and guanosine triphosphate (GTP) takes its place.
- Cascade initiation. The formation of the Ras-GTP complex signifies full protein activation. It detaches from the primary complex and associates with the Raf protein (MAP kinase kinase kinase) in the juxtamembrane region.
- Phosphorylation chain. The resulting Ras-GTP • Raf complex acquires protein kinase activity. Raf phosphorylates the MEK kinase enzyme. The activated MEK kinase, in turn, phosphorylates MAPK itself at two specific amino acid residues—threonine and tyrosine.
Biological Effects of MAPK
The attachment of a phosphate group ($-PO_3^{2-}$) to MAPK using ATP energy alters its electrical charge and conformation, converting the enzyme into its active state. Active MAPK phosphorylates its targets strictly at serine and threonine residues. The effects are distributed along two main pathways:
- Rapid response (cytosolic and membrane). MAPK alters the activity of various cytosolic and membrane proteins. This leads to the rapid regulation of ongoing metabolic rates and modifications in membrane translocase function.
- Slow, long-term response (nuclear). Phosphorylation increases MAPK's affinity for nuclear regulatory proteins (transcription factors). Signal translocation to the nucleus alters gene expression, ultimately regulating the mitotic activity of target cells—their growth and division.
Medical Significance: Ras Protein and Targeted Therapy
For normal function and receptor interaction, the Ras protein must be localized to the inner surface of the plasma membrane. This is ensured by acylation—the attachment of a specific lipid 'anchor' (a farnesyl group).
The oncological problem: Tumor cells frequently harbor Ras mutations that lock the protein in a constitutively active state. This causes ceaseless transmission of proliferative signals to the nucleus and uncontrolled cell division.
Pharmacological target: Modern targeted cancer therapies act as inhibitors of farnesyltransferase, the enzyme that attaches the lipid anchor to Ras. Without this tail, the mutant protein cannot anchor to the membrane. It remains in the cytosol, the signaling chain from growth factor receptors to the nucleus is broken, and tumor growth is halted.