Cell Cycle and CDK Paragraphs

Question 1

🧩 6. Ras/MAPK Pathway and the Restriction Point

Answer 1

The Ras/MAPK signalling pathway plays a critical role in driving cells through the G1 phase and past the Restriction Point, linking extracellular growth signals to intracellular cell cycle regulators. This pathway is initiated when mitogens such as EGF or PDGF bind to their receptors — typically receptor tyrosine kinases (RTKs) — on the cell surface. Ligand binding leads to RTK dimerisation and autophosphorylation, which creates docking sites for adaptor proteins. Grb2, containing an SH2 domain, binds to the phosphorylated receptor, while its SH3 domain recruits Sos, a guanine nucleotide exchange factor (GEF). Sos activates Ras, a small GTPase, by promoting the exchange of GDP for GTP.

Activated Ras then initiates a kinase cascade: it activates Raf, which phosphorylates MEK, which in turn phosphorylates ERK (MAP kinase). Phosphorylated ERK translocates to the nucleus and activates transcription factors like Jun, Fos, and Myc. These promote expression of early response genes, including Cyclin D, which forms complexes with CDK4/6 to phosphorylate Rb. This ultimately leads to E2F activation and transcription of S-phase genes, pushing the cell beyond the restriction point. Because this cascade integrates external cues and is tightly regulated, its dysregulation (e.g., constitutive Ras activation) is a frequent driver of cancer.