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Lecture 23 Signal Transduction 2. Major Concepts. Receptor tyrosine kinases control cell metabolism and proliferation Growth factor signaling through Ras Mutated cell signaling genes in cancer cells are called oncogenes Insulin signaling through PI-3 kinase

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major concepts
Major Concepts
  • Receptor tyrosine kinases control cell metabolism and proliferation
    • Growth factor signaling through Ras
    • Mutated cell signaling genes in cancer cells are called oncogenes
    • Insulin signaling through PI-3 kinase
  • TNF receptors activate protein complexes that control cell death and survival
slide3
Chronic myelogenous leukemia (CML) cells
  • Chromosomal rearrangement leads to expression of a unique signaling kinase (Bcr-Abl) required for the leukemia cells to survive
  • Gleevec inhibits Bcr-Abl kinase, cells die through apoptosis
receptor protein tyrosine kinases
Receptor Protein Tyrosine Kinases

(EGF, Epidermal growth factor)

Courtesy: Roger Miesfeld

receptor protein tyrosine kinases6
Receptor Protein Tyrosine Kinases

1) Receptor tyrosine kinases transmit extracellular signals by ligand-activation of an intrinsic tyrosine kinase function encoded in the cytoplasmic tail of the receptor.2) Activation of the intrinsic tyrosine kinase activity requires receptor dimerization, which is often stimulated, or at least stabilized, by ligand binding.3) Autophosphorylation of tyrosine residues within the receptor creates phosphotyrosine docking sites for signaling proteins that establish a relay signal between the receptor and a downstream phosphorylation cascade.

drosophila eyes and cancer are connected
Drosophila eyes and cancer are connected?
  • Activated EGF receptor with intrinsic tyrosine kinase
  • Adaptor protein Grb2 binds EGF receptor dimers
  • Recruitment of SOS
  • Activation of Ras (inactivation by RasGAP)
  • Ras-Raf complex formation
  • Src phosphorylates Raf
  • Raf phosphorylates MEK
  • MEK phosphorylates ERK
  • ERK dimerizes and then phosphorylates ELK
  • SRF binds phosphorylated ELK
  • Initiation of transcription leads to cell proliferation
slide8

In “Sevenless” mutant, the R7 photoreceptor does not differentiate properly, leading to no R7 cell, hence the name.

SOS (Son of sevenless) is downstream in pathway, interacts with Sevenless

BOSS (self explanatory) is ligand from neighboring cell that binds to and turns on Sevenless in developing eye

You can read more at:

http://www.sdbonline.org/fly/aimorph/eye.htm

back to cancer receptor protein tyrosine kinases
Back to Cancer:Receptor Protein Tyrosine Kinases

(EGF, Epidermal growth factor)

Courtesy: Roger Miesfeld

grb2 binds to phosphotyrosines on activated egf receptor sevenless
Grb2 binds to phosphotyrosines on activated EGF receptor (Sevenless)
  • Src homology domain, or SH2 domain
  • phosphotyrosine binding pocket and a separate specificity pocket

EGF Receptor

(Sevenless class)

Courtesy: Roger Miesfeld

sos son of sevenless connects grb2 to ras activates ras
SOS (Son of Sevenless) connects Grb2 to Ras, activates Ras

SH3 domain

Courtesy: Roger Miesfeld

SOS is a guanine nucleotide exchange factor (GEF)

ras src activate phosphorylation cascade
Ras/Src activatephosphorylation cascade

MAP kinase family:

Raf

MEK

ERK

gtpase activating proteins gap such as rasgap bind to ras and stimulate gtp hydrolysis
GTPase activating proteins (GAP) such as RasGAP bind to Ras and stimulate GTP hydrolysis

Courtesy: Roger Miesfeld

Turn off that signal!!

oncogenes just turn me on
Oncogenes just turn me on
  • Many “oncogenes” (oncology is the study of cancer), interfere with feedback inhibition of growth factor signaling pathways.
  • Gain of function mutations
  • Ras (rat sarcoma virus oncogene) may be involved in 30% of human cancers
  • Src (Roux sarcoma virus oncogene)
most common ras activating mutation
most common Ras activating mutation

glycine to valine mutation at codon 12 (G12V)

disrupts the intrinsic GTPase activity

Courtesy: Roger Miesfeld

insulin signaling is similar to egf signaling
Insulin signaling is similar to EGF signaling

IRS: insulin receptor substrate proteins

Courtesy: Roger Miesfeld

what in the world is tnf
What in the world is TNF?
  • Tumor Necrosis Factor
    • an inflammatory cytokine
    • a signaling molecule that induces apoptosis
  • Apoptosis is cell death through “falling apart”
    • Apoptotic bodies
    • Engulfed by surrounding cells to clean up debris
  • TNF Binds to a trimeric membrane receptor
    • Initiates 2 or more pathways, depending on the cell conditions
to be or not to be
To be or not to be…

Courtesy: Roger Miesfeld

signal transduction through tnf receptor family
Signal transduction through TNF receptor family
  • Adaptor complex formation
  • TNF R1 receptor is activated by TNF-alpha
  • 80 amino acid structural motif in the cytoplasmic tail of receptor called a Death Domain (DD) interacts with DDs on other proteins
  • The fate of the cell rests in the relative abundance (and activities) of proteins in two separate, but inter-related, signaling pathways.
slide21

Cell survival and cell death are opposing pathways

FADD binding to procaspase 8 stimulates an autocleavage reaction leading to cell death

TRAF2 binding to TRADD recruits the NFkB-inducing kinase (NIK) leading to cell survival

Ratio of FADD/Caspase 8 to TRAF2, RIP and NFkB determines cell fate

Courtesy: Roger Miesfeld