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Signal Transduction Pathway Smorgasbord Ron Bose, MD PhD Biochemistry and Molecular Cell Biology Programs Washington University School of Medicine Molecular Cell Biology Lecture. Oct 31, 2013
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Outline 1.Nuclear Hormone Receptors 2.Cytokine Receptors – JAK/STAT Pathway 3.PI3-kinase – Akt – mTOR 4.Regulation of Protein Kinases
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Resources: Nuclear Hormone Receptors http://www.nursa.org/index.cfm http://www.nursa.org/template.cfm?threadId=113 20 http://www.nursa.org/flash/gene/nuclearreceptor/s tart.html
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Nuclear Hormone Receptor Superfamily 1.48 Human genes 2.Major Categories: Knock-out in mice causes reproductive, developmental, or metabolic abnormalities. Thyroid Hormone Receptor (TR)- like TR, RAR, PPAR, Vitamin D receptor, LiverX Receptor Estrogen Receptor (ER)- like ER, PR, AR, Estrogen Receptor Related, Glucocorticoid receptor, Mineralocorticoid receptor Retinoid X Receptor (RXR) like RXR, Hepatocyte nuclear factor-4, etc.
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AF: Activation Function. Mediate transcriptional activation DNA Binding Domain Ligand Binding Domain www.nursa.org/
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AF: Activation Function. Mediate transcriptional activation www.nursa.org/
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Bind as homodimers Bind as heterodimers with RXR Hormone response elements are inverted repeats. Hormone response elements are direct repeats.
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Ligand Present Ligand Absent www.nursa.org/
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Movie: http://www.nursa.org/flash/gene/nuclearreceptor/start.htmlhttp://www.nursa.org/flash/gene/nuclearreceptor/start.html Tab 12. Nuclear Hormone Action Model www.nursa.org/
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Outline 1.Nuclear Hormone Receptors 2.Cytokine Receptors – JAK/STAT Pathway 3.PI3-kinase – Akt – mTOR 4.Regulation of Protein Kinases
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Cytokine Receptors – JAK/STAT Pathway Baker et al., Oncogene (2007) 26, 6724–6737
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Cytokine Receptors Baker et al., Oncogene (2007) 26, 6724–6737
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JAK = Janus kinases Baker et al., Oncogene (2007) 26, 6724–6737 4 genes in humans and mice TYK2 (first gene in this family to be identified) JAK1, JAK2, JAK3
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STAT= Signal Transducers and Activators of Transcription Baker et al., Oncogene (2007) 26, 6724–6737
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Cytokine Receptors – JAK/STAT Pathway Baker et al., Oncogene (2007) 26, 6724–6737
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from Marmor, Skaria, and Yarden 2004 Recptor Tyrosine Kinases Examples– EGFR, Her2, etc
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Outline 1.Nuclear Hormone Receptors 2.Cytokine Receptors – JAK/STAT Pathway 3.PI3-kinase – Akt – mTOR 4.Regulation of Protein Kinases
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PI3-kinase – Akt – mTOR Songet al., Nature Rev Mol Cell Bio 2012
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PI3-kinase – Akt PtdIns(4,5)P 2 (PIP2) PtdIns(3,4,5)P 3 (PIP3) PI3K PTEN Akt PDK1 Zoncu et al., Nature Rev Mol Cell Bio 2011
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mTOR complexes mTORC1 Rapamycin sensitive Responds to nutrient level, growth factors, energy, and stress. mTORC2 NOT rapamycin sensitive Inputs into mTORC2 less well known. Zoncu et al., Nature Rev Mol Cell Bio 2011
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mTORC1 substrates S6 kinase 1 (S6K1) eIF-4E binding protein (4E-BP) Zoncu et al., Nature Rev Mol Cell Bio 2011
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mTORC2 substrates Akt Zoncu et al., Nature Rev Mol Cell Bio 2011 PH domain Kinase Domain PDK1 mTORC2 S473T308 Downstream substrates: TSC complex, PRAS40, etc. 1 3 2
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Bringing it all together Zoncu et al., Nature Rev Mol Cell Bio 2011 mTOR is a signal integrator, like the chips and circuits in your smart phone
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Outline 1.Nuclear Hormone Receptors 2.Cytokine Receptors – JAK/STAT Pathway 3.PI3-kinase – Akt – mTOR 4.Regulation of Protein Kinases
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Manning et al., Science 2002
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Regulation of Protein Kinases 1.Post-translation modifications. Phosphorylation-dependent Activation Loop 2.Protein-protein interactions Regulatory Subunits Dimers
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Structure of PKA catalytic domain C Helix N-lobe C-lobe Helices Sheets Caplan, Science STKE 2005
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Illustration from Nolen et al, Mol. Cell, Vol. 15, p.661-675, 2004 Structural features of the PKA Activation Loop
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Phosphorylation of the MAP Kinase activation loop Phosphorylation on threonine and tyrosine Phospho-Thr 183 contacts -C and promotes active conformation Phospho-Thr 183 promotes ERK2 dimerization via conformational changes in C-terminal extension Illustration taken from Huse and Kuriyan, Cell 109, 275-282 (2002) AKT phosphorylation at T308 is also Activation Loop Phosphorylation
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Unphosphorylated MAP Kinase Structure Thr183 Tyr185 Canagarajah et al Cell 90, 859-869 (1997) Phosphorylated
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Thr183 Tyr185 Canagarajah et al Cell 90, 859-869 (1997) Unphosphorylated MAP Kinase Structure Phosphorylated
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Cyclin - Cyclin-dependent kinase (CDK) Complex Cyclin-dependent kinase (Cdk2) Cyclin A Jeffrey et al Nature 376, 313-320 (1995)
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Cdk2Cdk2.CyclinA Jeffrey et al Nature 376, 313-320 (1995) C-helix Activation Loop
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Asymmetric Dimer Formed by the EGFR Kinase Domain EGFR kinase domain asymmetric dimer Zhang, Gureasko, Shen, Cole, and Kuriyan. Cell 2006
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Summary 1.Nuclear hormone receptors consist of a DNA- binding domain and ligand-binding domain. 2.Cytokine receptors signal through the JAK kinases, which have 2 kinase domains, and the STAT transcription factors. 3.mTOR is a signal integrator for metabolic and growth factor signaling. 4.Protein kinases are regulated by PTM’s and protein-protein interactions.
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