MAP kinase cascade

Signal initiation and receptor complex assembly

The signal transduction process begins at the surface of the cell's plasma membrane. Initiators include various growth factors, such as epidermal growth factor (EGF) or nerve growth factor (NGF).

1. Ligand binding and receptor activation. The growth factor interacts with a specific receptor (receptor tyrosine kinase). This leads to receptor dimerization—the joining of its two subunits. Immediately following this, transautophosphorylation occurs: the receptor attaches phosphate groups to tyrosine residues in its own cytosolic (internal) portion.
2. Recruitment of adapter proteins. Phosphorylation dramatically alters the spatial conformation of the receptor, repeatedly increasing its affinity for the membrane adapter protein Grb2.
3. Interaction with the exchange factor. The binding of Grb2 to the receptor creates conditions for the binding of the cytosolic protein SOS, which acts as a guanine nucleotide exchange factor. As a result, a multicomponent complex is formed on the inner side of the membrane.

Ras protein activation and triggering 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 is firmly "anchored" in the cell membrane.

• Nucleotide exchange. The SOS protein within the receptor complex increases complementarity to Ras and induces a conformational change. As a result, the affinity of Ras for GDP drops sharply, GDP detaches, and guanosine triphosphate (GTP) takes its place.
• Cascade triggering. The formation of the Ras-GTP complex signifies full protein activation. It detaches from the primary complex and binds to the Raf protein (MAP kinase kinase kinase) in the perimembrane region.
• Phosphorylation chain. The resulting Ras-GTP • Raf complex acquires protein kinase activity. Raf phosphorylates the MEK enzyme kinase. The activated MEK kinase, in turn, phosphorylates MAP kinase itself at two specific amino acid residues—threonine and tyrosine.

Biological effects of MAP kinase

The attachment of a phosphate group ($-PO_3^{2-}$) to MAP kinase using ATP energy changes its electrical charge and conformation, converting the enzyme into an active state. Active MAP kinase phosphorylates its targets strictly at serine and threonine residues. The effect is distributed along two main pathways:

• Rapid response (cytosolic and membrane). MAP kinase alters the activity of various cytosolic and membrane proteins. This leads to the rapid regulation of ongoing metabolic processes and changes in the functioning of membrane translocases.
• Slow, long-term response (nuclear). Phosphorylation increases the affinity of MAP kinase for nuclear regulatory proteins (transcription factors). Translocation of the signal to the nucleus leads to changes in gene expression, which ultimately regulates the mitotic activity of target cells—their growth and division.

Medical significance: Ras protein and targeted therapy

For normal functioning and interaction with the receptor, the Ras protein must be localized on the inner surface of the plasma membrane. This is ensured by acylation—the attachment of a special lipid "anchor" (farnesyl residue).

The core issue in oncology: Mutations of the Ras protein are frequently detected in tumor cells, causing it to remain in a constantly active state. This induces incessant proliferative signaling 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 is unable to anchor to the membrane. It remains in the cytosol, the signaling chain from growth factor receptors to the nucleus is severed, and tumor growth stops.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Detailed structure and conformational changes of receptor tyrosine kinases
• Role and structure of the Grb2 membrane adapter protein
• Mechanism of action of the SOS protein as a guanine nucleotide exchange factor
• Specific nuclear transcription factors activated by MAP kinase
• Classification and functions of membrane translocases regulated by the cascade

Other topics in «Structure and Functions of Biological Membranes»

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