L5 - Cytokine Receptors

• Cytokines:

  • Broad range of cell signalling molecules
  • Proteins, peptides & glycoproteins (proteins w/ sugars on them)
  • Involved in autocrine, paracrine & endocrine signalling
  • Communicate w/ many cells
  • Immune system = only part of the story
• Cytokines:

  • Originally associated with the immune system, includes interferons (IFN) & interleukins (IL) + additional factors
  • IFN respond to viruses; IL respond to infection or cell damage
  • Starting point of cytokines: only part of story, lot more, reducing & receiving cytokines
  • Fibroblast, immune system not MAIN job, structural job, same w/ endothelial cells → also produce cytokines
• Cytokines:

  • Cytokines act via cell surface receptors
  • Definition - defining feature
  • Pretty much any cell can make or receive a cytokine
  • Cytokine receptor is what is special rather than the signal
• Cytokines:

  • Multiple subtypes w/ similar mechanisms
  • Different families of cytokine receptors
  • IL: βc = its receptor; IFR: go through different receptor
• Cytokines Lab:

  • Our lab will focus on growth hormone (GH)
  • Receptor for things that don’t sound like cytokines (immune system) but not how it is defined; eg EPO helps production of new RBC
• Growth Hormone:

  • Peptide hormone (also called somatotropin) produced by somatotropic cells in the anterior pituitary
  • Release increased by GHRH from the hypothalamus & ghrelin from the stomach (released when wanted)
  • Release inhibited by GH-inhibiting hormones (SS) also from the hypothalamus
  • GH has anabolic effects on the body (including muscle & bone growth)
  • Actions on liver, liver respond changing metabolism & releasing signal IGF-1 (favours growth)
  • Many GH actions are secondary to its ability to stimulate insulin-like growth factor 1 (IGF-1) release from the liver
• Cytokine Receptor:

  • No channel just a protein through membrane that work as pairs
  • GHR won’t do anything until it finds its pair - 2 receptor = dimortising, 2 halfs together
  • Inside protein kinases; JAKs put phosphate on other proteins cause protein to change shape (normally), this one puts tyrosine (big molecule) on it
  • Creates a flag on protein
  • Creates a recognition signal
• Growth hormone receptor signalling:

  • STAT5 part of the GH signalling pathway
  • STAT5 exists as 2 closely related forms STAT5a & STAT5b
  • Do different things
  • When phosphorylated by JAK2 phospho-STAT5 (pSTAT5) may form homo or heterodimers
  • Creates diversity
  • Once in the nucleus the pSTAT5 dimers interact w/ a transcription factor (GR) which is activated by glucocorticoids to turn on specific genes
  • Bind to site on gene to turn on particular proteins
  • Intracellular negative feedback pathways now turn off the pSTAT5 response
• There are multiple STATs (Signal Tranducers & Activators of Transcrption) associated with different receptors

  • Exist in cell where don’t do anything = latent; phosphorylated by GHR
• Growth Hormone Dimers:

  • GH brings 2 halfs together = dimers
  • Homodimers
  • same
  • Heterodimers
  • a & b
• Cytokine Receptors:

  • Respond to lots of things
  • Growth hormone binds to 2 receptor monomers & brings them together
  • & causes them to dimerize; JAK now in contact together & now turn on (become active)
  • JAKs phosphorylate the STAT5 proteins which then form dimers
  • STAT5 dimers translocate to the nucleus via nuclear pore
  • Nucleus ← Change gene transcription
  • Now transcription factors
  • Nucleus → Change protein expression
  • Many proteins can change
  • Now release IGF-1 → do growth stuff
  • Other pathways w/ other effects
  • Other branches of the growth hormone signalling pathway regulate cytoplasmic events
• Latent = not turned on

  Active form = dimers (pairs)

  • Dimerise JAK proteins to become active (to be protein kinases)