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Signal Transduction Pathway Smorgasbord

Molecular Cell Biology Lecture. Oct 31, 2013. Signal Transduction Pathway Smorgasbord. Ron Bose, MD PhD Biochemistry and Molecular Cell Biology Programs Washington University School of Medicine. Outline. Nuclear Hormone Receptors Cytokine Receptors – JAK/STAT Pathway

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Signal Transduction Pathway Smorgasbord

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  1. Molecular Cell Biology Lecture. Oct 31, 2013 Signal Transduction Pathway Smorgasbord Ron Bose, MD PhD Biochemistry and Molecular Cell Biology Programs Washington University School of Medicine

  2. Outline • Nuclear Hormone Receptors • Cytokine Receptors – JAK/STAT Pathway • PI3-kinase – Akt – mTOR • Regulation of Protein Kinases

  3. Resources: Nuclear Hormone Receptors http://www.nursa.org/index.cfm http://www.nursa.org/template.cfm?threadId=11320 http://www.nursa.org/flash/gene/nuclearreceptor/start.html

  4. Nuclear Hormone Receptor Superfamily • 48 Human genes • Major Categories: Knock-out in mice causes reproductive, developmental, or metabolic abnormalities.

  5. AF: Activation Function. Mediate transcriptional activation DNA Binding Domain Ligand Binding Domain www.nursa.org/

  6. AF: Activation Function. Mediate transcriptional activation www.nursa.org/

  7. Bind as homodimers Bind as heterodimers with RXR Hormone response elements are inverted repeats. Hormone response elements are direct repeats. www.nursa.org/

  8. Ligand Present Ligand Absent www.nursa.org/

  9. Movie: http://www.nursa.org/flash/gene/nuclearreceptor/start.html Tab 12. Nuclear Hormone Action Model www.nursa.org/

  10. Outline • Nuclear Hormone Receptors • Cytokine Receptors – JAK/STAT Pathway • PI3-kinase – Akt – mTOR • Regulation of Protein Kinases

  11. Cytokine Receptors – JAK/STAT Pathway Baker et al., Oncogene (2007) 26, 6724–6737

  12. Cytokine Receptors Baker et al., Oncogene (2007) 26, 6724–6737

  13. JAK = Janus kinases • 4 genes in humans and mice • TYK2 (first gene in this family to be identified) • JAK1, JAK2, JAK3 Baker et al., Oncogene (2007) 26, 6724–6737

  14. STAT= Signal Transducers and Activators of Transcription Baker et al., Oncogene (2007) 26, 6724–6737

  15. Cytokine Receptors – JAK/STAT Pathway Baker et al., Oncogene (2007) 26, 6724–6737

  16. Recptor Tyrosine Kinases Examples– EGFR, Her2, etc from Marmor, Skaria, and Yarden 2004

  17. Outline • Nuclear Hormone Receptors • Cytokine Receptors – JAK/STAT Pathway • PI3-kinase – Akt – mTOR • Regulation of Protein Kinases

  18. PI3-kinase – Akt – mTOR Songet al., Nature Rev Mol Cell Bio 2012

  19. PI3-kinase – Akt PI3K PtdIns(4,5)P2 (PIP2) PtdIns(3,4,5)P3 (PIP3) PTEN PDK1 Akt Zoncu et al., Nature Rev Mol Cell Bio 2011

  20. 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

  21. mTORC1 substrates • S6 kinase 1 (S6K1) • eIF-4E binding protein (4E-BP) Zoncu et al., Nature Rev Mol Cell Bio 2011

  22. mTORC2 substrates Akt mTORC2 PDK1 1 2 T308 S473 PH domain Kinase Domain 3 Downstream substrates: TSC complex, PRAS40, etc. Zoncu et al., Nature Rev Mol Cell Bio 2011

  23. Bringing it all together mTOR is a signal integrator, like the chips and circuits in your smart phone Zoncu et al., Nature Rev Mol Cell Bio 2011

  24. Outline • Nuclear Hormone Receptors • Cytokine Receptors – JAK/STAT Pathway • PI3-kinase – Akt – mTOR • Regulation of Protein Kinases

  25. Manning et al., Science 2002

  26. Regulation of Protein Kinases • Post-translation modifications. • Phosphorylation-dependent • Activation Loop • Protein-protein interactions • Regulatory Subunits • Dimers

  27. C Helix Structure of PKA catalytic domain a Helices b Sheets N-lobe C-lobe Caplan, Science STKE 2005

  28. Structural features of the PKA Activation Loop Illustration from Nolen et al, Mol. Cell, Vol. 15, p.661-675, 2004

  29. 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 AKT phosphorylation at T308 is also Activation Loop Phosphorylation Illustration taken from Huse and Kuriyan, Cell 109, 275-282 (2002)

  30. MAP Kinase Structure Thr183 Tyr185 Unphosphorylated Phosphorylated Canagarajah et al Cell 90, 859-869 (1997)

  31. MAP Kinase Structure Unphosphorylated Thr183 Phosphorylated Tyr185 Canagarajah et al Cell 90, 859-869 (1997)

  32. Cyclin - Cyclin-dependent kinase (CDK) Complex Cyclin A Cyclin-dependent kinase (Cdk2) Jeffrey et al Nature 376, 313-320 (1995)

  33. Jeffrey et al Nature 376, 313-320 (1995) C-helix C-helix Activation Loop Activation Loop Cdk2 Cdk2.CyclinA

  34. Asymmetric Dimer Formed by theEGFR Kinase Domain EGFR kinase domain asymmetric dimer Zhang, Gureasko, Shen, Cole, and Kuriyan. Cell 2006

  35. Summary • Nuclear hormone receptors consist of a DNA-binding domain and ligand-binding domain. • Cytokine receptors signal through the JAK kinases, which have 2 kinase domains, and the STAT transcription factors. • mTOR is a signal integrator for metabolic and growth factor signaling. • Protein kinases are regulated by PTM’s and protein-protein interactions.

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