Chapter 16: Growth Factor & Cytokine Signaling

Growth Factor & Cytokine Signaling begins by elucidating the activation of Receptor Tyrosine Kinases (RTKs), describing how ligand-induced dimerization leads to cross-phosphorylation and the recruitment of signaling proteins via SH2 domains, exemplified by the HER/ErbB family. A central focus is placed on the Ras/MAP Kinase pathway, detailing the sequential activation of the small GTPase Ras by GEFs like Sos, followed by the phosphorylation cascade involving Raf, MEK, and MAP kinase (ERK) to modulate early response genes. The narrative expands to phosphoinositide signaling, explaining how PI-3 kinase generates lipid docking sites for Protein Kinase B (PKB/Akt) to promote cell survival, a process counteracted by the tumor suppressor PTEN. Cytokine receptor signaling is analyzed through the JAK/STAT pathway, where receptor-associated JAK kinases phosphorylate STAT transcription factors, with attention to negative feedback loops involving SOCS proteins and phosphatases. The text also covers the TGF-beta superfamily, where receptor serine/threonine kinases activate Smad complexes to regulate development and matrix production. Furthermore, the summary distinguishes signaling mechanisms relying on irreversible protein cleavage, such as the Notch/Delta pathway involving ADAM proteases and gamma-secretase. Finally, it explores pathways controlled by ubiquitin-mediated proteolysis, including the canonical Wnt pathway stabilizing beta-catenin, Hedgehog signaling involving primary cilia and the relief of transcriptional repression, and the NF-kappaB pathway where signalosomes trigger the degradation of inhibitors to unleash immune responses.