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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 Receptor-Linked Kinases

  • 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 Receptor-Linked Kinases

GAP

Grb2,Shc

GEF like Sos

RTK- Ras - MAPK Pathway



Insulin triggers uptake of glucose how
Insulin Triggers Uptake of Glucose – How? Receptor-Linked Kinases

Fig 29-7


Src the prototypical non receptor tyrosine kinase
Src – The Prototypical Non-Receptor Tyrosine Kinase Receptor-Linked Kinases

  • 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 Receptor-Linked Kinases

phosphotyrosine binding domains

Adaptors: Masters of their Domains

Fig 27-12

Fig 27-11


Fig 27-11 Receptor-Linked Kinases


Small monomeric gtpases
Small Monomeric GTPases Receptor-Linked Kinases

  • 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


Activation cycle of gtpase
Activation Cycle of GTPase Receptor-Linked Kinases

Fig27-8


Gaps gefs
GAPs & GEFs Receptor-Linked Kinases

  • 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 Receptor-Linked Kinases

  • 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-Linked Kinases

  • 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


T cell receptor mediated lymphocyte activation
T-cell-Receptor-Mediated Lymphocyte Activation Receptor-Linked Kinases

Fig29-8


Cytokines activate jak stat pathway
Cytokines Activate JAK-STAT Pathway Receptor-Linked Kinases

Fig 29-9


Rs tk signal transduction components
RS/TK Signal Transduction Components Receptor-Linked Kinases

  • 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


Ligands of tgf superfamily activate smad pathway
Ligands of TGF- Receptor-Linked Kinases Superfamily Activate Smad Pathway

Fig 29-10


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