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

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.