11-12-24 [Signaling pathways that control gene expression] [Munmun] (1)

Growth Factor and Cytokine Signaling Pathways

  • Control gene expression through various pathways.

  • Led by ligands, receptors, and signal transduction proteins.

  • Associated with metabolic cell phenotype responses.

Overview of Signaling Pathways

  • Growth Factors and Their Receptor Tyrosine Kinases.

  • The Ras/MAP Kinase Signal Transduction Pathway.

  • Phosphoinositide Signal Transduction Pathways.

  • Cytokine Receptors (JAK/STAT pathway).

  • TGF-β Family and Smad Transcription Factors.

  • Pathways involving regulated protein cleavage (Notch/Delta, EGF precursors).

  • Signaling through proteasomal degradation of components (Wnt, Hedgehog, NF-κB).

Cell-Surface Receptors and Signal Transduction (1)

  • Pathway activation through various pathways (A, B, C, D).

  • GRB2 or Shc, proteins interacting with Phospholipase C.

  • Involvement of proteins like Ras increases Ca²+ levels.

  • Signal transduction includes both activation and repression of genes through modification of proteins.

Cell-Surface Receptors and Signal Transduction (2)

  • Various pathways (A to D) activate different responses involving GPCRs, TGF-β, Notch/Delta, and others.

Transcription Factor Regulation

  • Gene expression's induction is dependent on the gene's epigenetic state.

  • Transition from closed chromatin (gene off) to open chromatin (gene on).

  • Signals lead to phosphorylation and acetylation changes affecting transcription states.

Receptor Tyrosine Kinases (RTK)

  • General structure includes a ligand-binding region and transmembrane helices.

  • Dimerization and activation occur upon ligand binding.

  • Autophosphorylation of cytoplasmic domain triggers downstream signaling pathways.

  • EGF family receptors include HER1-4, bind to various ligands including EGF, TGF-α, and others.

Activation of EGF Receptor

  • Ligand-bound dimers cause conformational changes, leading to autophosphorylation

  • The activation of kinase domains initiates phosphorylation cascades transforming signals to the nucleus.

Ras/MAP Kinase Signal Transduction Pathway

  • Activation through receptor tyrosine kinases recruiting GRB2 and SOS.

  • Ras switches between GDP-bound (inactive) and GTP-bound (active) states, mediating further signaling.

Gene transcription induction by MAPK

  • MAPK activates transcription factors that regulate cell-specific pathways across various cellular functions.

Scaffold Proteins

  • Scaffold proteins maintain separation among signaling pathways ensuring specificity.

Cytokine Signaling and JAK/STAT Pathways

  • Cytokines promote differentiation and cell proliferation (e.g., EPO for erythroid progenitors).

  • JAK2's kinase activity and phosphorylation events regulate pathways leading to transcriptional activation via STAT proteins.

Regulation of Cytokine Signaling

  • Short-term regulation involves SHP1 phosphatase deactivating JAK2.

  • Long-term regulation through SOCS proteins that mediate degradation of signaling components.

TGF-β Family of Growth Factors

  • Function in development and regulate gene transcription through SMAD proteins.

  • Activate through serine kinase receptors leading to complex formation and nuclear translocation.

Notch/Delta Signaling Pathway

  • Regulates cell fate through proteolytic cleavage releasing transcription factors that modulate transcription in the nucleus.

Proteasomal Degradation in Signaling

  • Wnt and Hedgehog pathways involve proteasomal pathways that are irreversible and control protein levels impacting various cellular functions.

  • NF-κB regulates immune responses and inflammatory signaling through similar mechanisms.

Conclusion

  • Understanding these signaling pathways is vital for insights into developmental biology, cancer, and cellular responses to external signals.