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Signal Transduction II. Transduction Proteins & Second Messengers. Major Signaling Highways. Growth Factor/Cytokine/Adhesion RTK RS/TK JAK FAKs Steroid Hormone Intracellular DNA binding proteins Virtually everything else 7-pass TM receptors.

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signal transduction ii

Signal Transduction II

Transduction Proteins & Second Messengers

major signaling highways
Major Signaling Highways
  • Growth Factor/Cytokine/Adhesion
    • RTK
    • RS/TK
    • JAK
    • FAKs
  • Steroid Hormone
    • Intracellular DNA binding proteins
  • Virtually everything else
    • 7-pass TM receptors
typical iconic domain representations and family groupings
Typical Iconic Domain Representations and Family Groupings

Non-Receptor

Receptor

Non-Receptor

Receptor

it s all about phosphorylation
It's All About Phosphorylation
  • RTKs and RS/TK directly phosphorylate each other and substrates upon ligand binding
  • Ligand activates linked TKs indirectly
  • 7TM receptors activate non-receptor S/T kinases
what goes on must come off
What goes on must come off
  • Phosphatase Families
signal transduction downstream of receptor kinases receptor linked kinases

Signal Transduction Downstream of Receptor Kinases & Receptor-Linked Kinases

Adaptors, Small GTPases, MAPKs

rtk signal transduction components
RTK Signal Transduction Components
  • The Receptor
  • Adaptors, GAPs, GEFs,
    • All contain SH2 (and usually SH3) domains (bind P-Y)
    • Adaptors
      • Shc, Grb2, Nck, Crk
    • GAPs
      • Ras-GAP, p120GAP
    • GEFs
      • Vav, SOS
    • Recruit/activate p21 GTPase family members – (Ras family)
      • Ras, Rho, Cdc42, Rac
  • PI3K, PLC,
    • Generate 2nd messengers
      • PI3K – phosphoinositols (PIP2, PIP3)
      • PLC - diacylglycerol (DAG)+ inositol phosphate (IP2, IP3)
rtk ras mapk pathway

GEF

GAP

Grb2,Shc

GEF like Sos

RTK- Ras - MAPK Pathway
src the prototypical non receptor tyrosine kinase
Src – The Prototypical Non-Receptor Tyrosine Kinase
  • SH1 – tyrosine kinase domain
  • SH2 – phosphotyrosine binding domain
  • SH3 – polyproline binding domain
  • SH2 and 3 domains have been found in many other signal transduction proteins and all have a conserved structure and functionality
  • SH1 domain found in all tyrosine kinases

Fig27-3E

adaptors masters of their domains

polyproline binding domains

phosphotyrosine binding domains

Adaptors: Masters of their Domains

Fig 27-12

Fig 27-11

small monomeric gtpases
Small Monomeric GTPases
  • Dramatically different conformations of proteins depending on ligand
    • GTP vs GDP
  • All have MW ~21KDa
    • p21
  • Ras Family
    • Ras, Rho, Cdc42
  • Rab family
    • Rab, Arf, Sar
  • See Table 27-3 for others

Fig 27-7

gaps gefs
GAPs & GEFs
  • Have adaptor domains (SH2, SH3, PH, PTB)
  • GEF – stimulate release of GDP from GTPase
  • GAP – stimulate hydrolysis of GTP by GTPase

Fig 27-12

activated ras triggers map kinase cascade
Activated Ras Triggers MAP Kinase Cascade
  • MAPK = Mitogen Activated Protein Kinases
    • ERK1, ERK2, etc = Extracellular signal Regulated Kinase
  • MAPK is activated by a kinase called variably MAPK Kinase (MAPKK) or MEK (MAPK/ERK Kinase)
  • MEK is activated by a kinase called Raf (Ras activated factor) (or MAPK Kinase Kinase)
  • Raf is activated by Ras – not clear how yet
tk linked signal transduction components
TK-Linked Signal Transduction Components
  • Receptor
  • Non-receptor tyrosine kinases
    • JAKs
      • Activate STATs (signal transducers and activators of transcription)
    • Src family members
      • Src, Yes, Fyn, Lck
      • Activated by T-cell receptors, focal adhesion kinases, and RTKs
rs tk signal transduction components
RS/TK Signal Transduction Components
  • Receptors
    • RII receptor binds ligand 1st & phosphorylates RI upon heterodimerization
    • RI in turn phosphorylates smads
  • Regulatory smads
    • Require phosphorylation by RI receptor
    • Interact with co-smad & translocate to nucleus
  • Inhibitory smads
    • Bind to regulatory smads and block heterodimerization with co-smads
  • Co-smads
    • Do not require phosphorylation
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