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Comprehensive Overview of the Ras/MAP Kinase Signaling Pathway in Cell Biology

Detailed exploration of the Ras/MAP kinase pathway, including RTK activation, Ras GTPase function, kinase cascades, and gene expression regulation relevant to cancer biology.

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Lecture 12 16.4 The Ras/MAP Kinase Pathway
The Ras/MAP kinase pathway • RTKs and cytokine receptors activate the intracellular GTPase switch protein Ras by recruiting GRB2 and SOS to the membrane through specific SH2 and SH3 interactions. • Ras is structurally similar to G⍺ subunits and functions as a small GTPase (G proteins are large GTPases). Mutations in Ras are found in over 25% of all cancers. In some types of cancer, mutations are found in over 90% of cases. • Guanine nucleotide exchange factors (GEFs such as SOS) and GTPase-activating proteins (GAPs) stimulate Ras to cycle between an inactive GDP-bound and an active GTP-bound form. • Ras activates a Raf-MEK-MAPK kinase cascade that activates MAPK activity. • MAPK phosphorylates transcription factors that turn on genes controlling various cell-specific pathways.
Raf (MAPKKK) MEK (MAPKK) ERK (MAPK) MAP Kinase Pathway • RTK activation leads to the activation of a MAP kinase cascade • The cascade culminates in the phosphorylation and activation of transcription factors controlling gene expression P P nucleus cytoplasm SH2 domain Ras GTP MEK MEK ERK ERK P P P P GRB2 SH3 domains Sos Raf ERK P P MAP kinase TCF TCF P cell membrane RTK ligand: growth factor Ras-GTP
Fig. 16-10: Activation of Ras
Binding of ligand (FGF) to the RTK (FGFR) leads to dimerization and autophosphorylation of the intracellular portions
Yankulov_MCB2050_lecture panel 4 6 Adapter proteins (GRB2 and Sos) link the RTK to Ras via SH2 and SH3 domains (more on those in the coming slides). GRB2 = Growth Factor Receptor –Bound Protein 2 Sos = Son of Sevenless (Sevenless is a gene discovered in fruit flies that, upon deletion, leads to the 7th of 8 photoreceptors in the ommatidium to fail to form)
SOS acts as a GEF (Guanine Exchange Factor) for Ras and allows it to activate downstream signaling pathways.
SH2 and SH3 Domains • SH2 domains allow the proteins that contain them to bind to phosphorylated tyrosine residues • SH3 domains bind to target proteins that have proline- rich sequenses
• many different SH2 domains exist • binding specificity is determined by the amino acids that surrounding the phosphorylated tyrosine (Y) residue Many signaling proteins that bind tyrosine kinase receptors contain conserved SH2 ad SH3 domains.
Fig 16-13: The Ras/MAP Kinase Pathway
Activation of Raf by Ras-GTP • 14-3-3 proteins bind to Raf and maintain it in an inactive conformation • Active Ras binds to Raf and leads to the dissociation of the 14-3-3 protein as well as a conformational change and activation of Raf Sos
Activation of MAPKK and MAPK by Raf Raf (MAPKKK) MEK (MAPKK) ERK (MAPK) Transcription Factors
Fig. 16-14: Induction of Gene Expression by MAP Kinase • MAPK can phosphorylate targets both inside and outside of the nucleus • MAPK has over 175 targets within the nucleus and regulates over 1100 genes