Explain the downstream signalling of RTKs

Receptor Tyrosine Kinases (RTKs) are special types of transmembrane receptors that help the cell to receive and process external signals like growth factors, insulin and other peptide hormones. These signals control very important cellular processes like cell division, cell growth, metabolism, and survival. When a signal molecule binds to the RTK, it activates a cascade of events inside the cell. This entire process is known as downstream signalling of RTKs.

There are five main steps in the downstream signalling of RTKs. The signal starts from ligand binding and proceeds until intracellular kinases activate target proteins.

Step 1: Ligand Binding and Receptor Dimerisation

The process begins when an extracellular signalling molecule such as epidermal growth factor (EGF) or insulin binds to the extracellular domain of RTK. Once the ligand binds, it causes dimerisation of the two RTK monomers. This means two receptor molecules come together and form a dimer.

This dimerisation brings the intracellular tyrosine kinase domains closer, which is important for the next step.

Step 2: Autophosphorylation of Tyrosine Residues

After dimerisation, the kinase domain of one RTK phosphorylates the tyrosine residues present on the other RTK, and vice versa. This process is called autophosphorylation. These phosphate groups attach to the tyrosine residues in the cytoplasmic region.

These phosphorylated tyrosines now serve as docking sites for specific intracellular signalling proteins that contain special domains like SH2 (Src homology 2) or PTB (phosphotyrosine-binding) domains.

Step 3: Recruitment of Adaptor Proteins

Now, specific adaptor proteins are recruited to the phosphorylated RTK. One important adaptor is Grb2 (Growth factor receptor-bound protein 2). Grb2 binds to the phosphotyrosine using its SH2 domain and also binds to SOS (Son of Sevenless) through its SH3 domains.

Grb2 does not work as an enzyme but it acts like a bridge to pass the signal to the next protein, which is Ras.

Step 4: Activation of Ras Protein

Now SOS, which is a guanine nucleotide exchange factor (GEF), activates Ras, a small GTPase present on the inner side of the plasma membrane. It does this by helping Ras to release GDP and bind GTP. This change activates the Ras protein.

Activated Ras is now ready to pass the signal to the MAPK cascade, which is the next major step in the pathway.

Step 5: Activation of MAPK Cascade

Activated Ras first activates Raf (a MAPKKK), which then activates MEK (a MAPKK), and finally ERK (a MAPK). This is called the MAP kinase cascade. Each step involves phosphorylation and amplification of the signal.

ERK (extracellular signal-regulated kinase), once activated, enters the nucleus and activates specific transcription factors, which finally causes changes in gene expression, cell division, survival and differentiation depending on the original signal.








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