In-Depth Notes on Cell Signalling

Cell Signalling Overview

G-Protein Coupled Receptors (GPCRs)

  • GPCRs are membrane proteins that play a vital role in cell signaling.
  • Major points about GPCRs:
    • A: There are many GPCRs in the human genome (not just a few).
    • B: Signal molecule binding leads to phosphorylation, allowing G-proteins to bind.
    • C: GPCRs act as guanine nucleotide exchange factors (GEFs) for specific G-proteins.
    • D: GPCRs are integral membrane proteins, typically not peripheral and made of multiple polypeptides.

GPCR Signaling Pathway

  • Overview: The process initiated by GPCR involves various second messengers like cAMP and IP3:
    • G-proteins activate enzymes which produce second messengers.
    • Main signaling molecules: cyclic AMP (cAMP), inositol triphosphate (IP3), diacylglycerol (DAG).
    • Responses include activation of genes, enzymes, and ion channels.
Major Families of Trimeric G Proteins
  • Four main families categorized by the α subunit:
    • Family I (G₁): Activates adenylyl cyclase; influences Ca²+ channels.
    • Family II: Inhibits adenylyl cyclase.
    • Family III: Activates phospholipase C-β (PLC-β).
    • Family IV (G12/13): Involved in K+ channel activation and cytoskeletal regulation.

Phospholipase C-B (PLC-β) Activation

  • PLC-β hydrolyzes PI(4,5)P2 into DAG and IP3.
  • Functions:
    • DAG: Recruits and activates Protein Kinase C (PKC).
    • IP3: Triggers Ca²+ release from the endoplasmic reticulum into the cytosol, increasing intracellular calcium levels.

Ca²+ as a Signaling Molecule

  • Ca²+ is pivotal in various cellular processes including:
    • Muscle contraction
    • Secretion
  • Ca²+ signals are often mediated by calmodulin-dependent protein kinases.

Enzyme-Coupled Receptors

  • Typically transmembrane proteins with an enzyme activity on the cytosolic side. Subtypes include:
    1. Receptor Tyrosine Kinases (RTKs): enzymes that phosphorylate tyrosine residues.
    2. Tyrosine-kinase-associated receptors
    3. Receptor serine/threonine kinases
    4. Histidine-kinase-associated receptors
    5. Receptor guanylyl cyclases
    6. Receptor-like tyrosine phosphatases
Activated Receptor Tyrosine Kinases (RTKs)
  • Phosphorylate themselves upon activation.
  • Activation mechanism includes ligand binding causing dimerization.
  • Dimerization leads to trans-autophosphorylation, generating docking sites for other signaling proteins.
Ras GTPase
  • Ras plays a crucial role in RTK signaling pathways.
  • Mediates signaling downstream of RTKs, linking to MAP kinase cascades which regulate cell proliferation.

JAK-STAT Pathway in Cytokine Signaling

  • Cytokine receptors activate Janus kinases (JAKs) instead of having intrinsic kinase activity.
  • JAKs phosphorylate the receptors, allowing STAT proteins to bind, dissociate, and regulate gene expression in the nucleus.

TGFβ Signaling Pathway

  • TGFβ receptors possess serine/threonine kinase activity.
  • Binding leads to receptor dimerization and phosphorylation of R-Smads, which regulate transcription in the nucleus.

Parallel Signaling Pathways and Interactions

  • Many pathways can intersect and affect common targets, highlighting the complexity of cell signaling.

Key Points of Interconnected Signaling Pathways

  • Not just RTKs mediate MAP kinase pathways - crosstalk is common.
  • Thousands of protein interactions within cells can impact cell behavior significantly.