RTK Paragraphs

Question 1

Introduction to Receptor Kinases

Answer 1

Receptor kinases are transmembrane proteins that translate extracellular signals into intracellular responses via ligand-induced phosphorylation cascades. The two main families in animal cells are Receptor Tyrosine Kinases (RTKs) and Serine/Threonine Kinase Receptors (STKRs). Though both initiate signalling by phosphorylating target proteins, they differ in structure, activation mechanism, and downstream effectors.

Question 2

Comparison of RTKs and Serine/Threonine Kinase Receptors
STRUCTURE

Answer 2

RTKs are single-pass transmembrane proteins with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain.
STKRs (e.g. TGF-β receptors) are usually heteromeric complexes: Type I and Type II receptors, both with serine/threonine kinase domains.

Question 3

Comparison of RTKs and Serine/Threonine Kinase Receptors
Activation Mechanism

Answer 3

RTKs are activated by ligand-induced dimerisation, which brings kinase domains together, allowing autophosphorylation on tyrosine residues.
STKRs activate when a ligand binds to the Type II receptor, which phosphorylates the Type I receptor, enabling it to signal downstream.

Question 4

Comparison of RTKs and Serine/Threonine Kinase Receptors
Downstream Signalling

Answer 4

RTKs recruit signalling proteins containing SH2 or PTB domains (e.g. Grb2, PI3K) that bind to phosphotyrosines.
STKRs signal mainly through Smad proteins, which are directly phosphorylated by the activated Type I receptor.

Question 5

Comparison of RTKs and Serine/Threonine Kinase Receptors
Functional Output

Answer 5

RTKs regulate cell proliferation, survival, and migration via cascades like Ras/MAPK, PI3K/Akt, and PLCγ.
STKRs (like the TGF-β family) typically control cell differentiation, apoptosis, and tissue homeostasis, often acting as tumour suppressors.

Question 6

Detailed Example: RTK-Driven Ras/MAPK Pathway

Answer 6

One of the best-characterised RTK signalling cascades is the Ras/MAPK pathway, activated by growth factors such as EGF or PDGF.
Ligand Binding and RTK Activation: A growth factor binds to the extracellular domain of the RTK, inducing dimerisation and autophosphorylation of specific tyrosine residues on the intracellular domain.
Recruitment of Grb2 and Sos: The adaptor protein Grb2 binds to phosphotyrosines via its SH2 domain, and uses its SH3 domains to recruit Sos, a guanine nucleotide exchange factor (GEF).
Activation of Ras: Sos activates Ras by facilitating GDP–GTP exchange. GTP-bound Ras is now active and initiates the kinase cascade.
MAPK Cascade: Active Ras recruits and activates Raf (MAPKKK), which phosphorylates and activates MEK (MAPKK), which in turn activates ERK (MAPK).
Cellular Response: ERK translocates into the nucleus, where it phosphorylates transcription factors like Elk-1 and c-Myc, promoting the expression of genes that drive S-phase entry, cell growth, and division.
This pathway is crucial in development and wound healing but, when mutated (e.g. Ras^G12V), it can lead to oncogenic transformation.