chapter 5 growth factors, receptors, and cancer the human egf receptor (her) signaling network
TRANSCRIPT
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CHAPTER 5Growth Factors, Receptors, and Cancer
The human EGF receptor (HER) signaling network.
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Normal metazoan (後生動物 ) cells control each other’s lives
Maintenance of tissue architecture.
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Storage of PDGF by platelets
Effects of growth factors on cells.
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The Src protein functions as a tyrosine kinase
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Actions of protein kinases
Substrate specificity of the Src kinase
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The EGF receptor functions as a tyrosine kinase
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Structure of tyrosine kinase receptors
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An altered growth factor receptor can function as an oncoprotein
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Deregulation of receptor firing
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A growth factor gene can become an oncogene: the case of sis
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Transphosphorylation underlies the operations of receptor tyrosine kinasesFormation of phosphotyrosine on the EGFR following ligand addition
Apparent autophosphorylation of EGFR
32PO4
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Receptor dimerization, ligand binding, transphosphorylation and glioblastoma pathogenesis
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Alternative mechanisms of growth factor-induced receptor dimerization.
homodimer
triple
Back-to-back
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Gene fusion causing constitutively dimerized receptors
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Multiple structural alterations affect Kit receptor firing.
GIST: gastrointestinal stromal tumor
AML: acute myelogenous leukemia
Kit receptor
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Yet other types of receptors enable mammalian cells to communicate with their environment
Structure of cytokine receptors.
Structure of the TGF-b receptor
Jaks (Janus kinases)Noncovalently attached
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Structure of the Notch receptor
Two successive proteolytic cleavages
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The Patched-Smoothened signaling system
Trapping Gli
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Canonical Wnt signaling via Frizzled receptors
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Non-canonical Wnt signaling via Frizzled receptors
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Nuclear receptors sense the presence of low–molecular–weight lipophilic ligands
Steroid sex hormones, retinoids, vitamin D
Estrogen, progesterone and androgen
RXR (retinoid X receptor)PPAR-g (peroxisome proliferator-activated receptor-g)
DES (E2 mimic diethylstibestrol)
Co-activatorsCo-repressors
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Extracellular matrixGlycoprotein, hyaluronan and proteoglycans
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Integrin receptors sense association between the cell and the extracellular matrix
Mg2+ , Mn2+ , Ca2+
a2b1 integrin- collagen I
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Integrin tethering to the ECM and cytoskeleton
Focal adhersionActin fiber
Intermediary protein
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Some integrins are essential for tumorigenesis
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The Ras protein, an apparent component of the downstream signaling cascade, functions as a G protein
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The structure of the Ras protein and its response to GTP binding.
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Alternative mechanisms of transformation by Ras.
5 min after EGF is added