Database connection Import model from BioModels.net Database connection Akira Funahashi Keio University, Japan Database connection Database connection Import model from BioModels.net Import model from JWS Online Database connection Database connection Import model from PANTHER Import model from PANTHER Database connection Comparison Import model from PANTHER •BioModels.net •Curated •Can simulate •No CellDesigner Layout •Panther DB •Curated •Can not simulate •CellDesigner Layout SABIO-RK CellDesigner ⇔ SABIO RK •Web-accessible database •Users can import additional information •http://sabio.h-its.org/ to each object (reaction) on-the-fly •Contains information about biochemical •SBML (Systems Biology Markup Language) reactions, related kinetic equations and is used to exchange information parameters CellDesigner E Name, EC number S P Vmax[S] Km +[S] kinetic law, parameters, function / unit definitions Integration Example •Import kinetic law, parameters to the model from SABIO-RK Example Example Example Example Example Annotating a model Akira Funahashi Keio University, Japan V IEWPOINT Peripheral insulin resistance contributes to Jnk1 in obese mice, or inhibition of serine mice increases insulin sensitivity, revealing type 2 diabetes, but ␤-cell failure is the es- kinases by salicylates, reduces Ser phosphor- targets for inhibitor design. However, inhibi- sential feature of all types of diabetes. ␤ cells ylation of IRS proteins and reverses hyper- tion of SHIP2 or pTEN might be risky be- frequently fail to compensate for insulin re- glycemia, hyperinsulinemia, and dyslipide- cause they stabilize PI(3,4,5)P3, which can sistance, apparently because the IRS2-branch mia in obese rodents by sensitizing insulin stimulate cell growth. By contrast, PTP1B of the insulin and IGF signaling cascade is signaling pathways (18). resides in the endoplasmic reticulum, where it also essential for ␤-cell growth, function, and Ubiquitin-mediated degradation of IRS1 dephosphorylates the insulin receptor during inter- survival (14). Increased expression of IRS2 and IRS2 also promotes insulin resistance nalization and recycling to the plasma membrane in ␤ cells promotes compensatory insulin secre- (Fig. 1). IL-6 secreted from leukocytes and (21). This specialized mechanism appears to limit tion in obese mice and prevents ␤-cell destruction adipocytes increases expression of SOCS dangerous side effects of PTP1B inhibitors. induced by streptozotocin—adrugthatinduces proteins, which are best known for their abil- The close association between obesity and type 1 diabetes; IRS2 also improves the survivalIGFity to inhibit cytokine signaling receptor signaling. insulin resistance, and their progression topathway type IGF signaling pathway and function of islet transplants in mice. Drugs However, SOCS1 and SOCS3 also recruit an 2diabetes,isaserioushealthproblem.Whether that increase IRS2 synthesis might be useful treat- elongin BC-based ubiquitin ligase into the better management of chronicReview inflammation can Trends in Pharmacological Sciences March 2012, Vol. 33, No. 3 ments for diabetes. For improve insulin action, example, expression of promote ␤I -cell func- Key: Induces the IRS2 gene in ␤ tion, andInsuli restoren IGF- centralI/II Hsp90 client RTK cells is increased by nervous system appe-transph osphorylation Inhibits Attenuated path agonists that stimulate tite control is an impor- I I adenosine 3Ј,5Ј-mono- tant area ofα investiga-α α α α α Plasma membrane β β β β β β PIP PIP phosphate (cAMP) tion. Finding drugs that 2 3 PIP3 PDK1 Shc P P production—including stimulate IRS2 synthe- P P P PI3K PDK1 P P P P Grb2 IRS-1/2 glucagon-like peptide– sis or promote its sig- SoS PTEN IR IGF- IR 1orglucoseitself— naling might be a good p53 through pathways that starting point. Howev- Ras Ras PKC P Raf-1 P GTP GDP activate the transcrip- er, too much insulin ac- MDM2 P PI3K pathway PI3K tion factor CREB (15) tion might be detrimen- P TSC2 on January 17, 2007 Akt P MEK1 P (Fig. 1). tal, so future work must TSC1 Understanding dys- better resolve the net- P ERK-1/2 P mTOR 4EBP1 FoxO3a P BAD P GSK-3β regulated insulin sig- work of insulin re- Raptor eIF4E (inactive) aling is an impor- sponses that are gener-pathway MAPK/ERK P Cytochrome C c-Myc P P Fas tant goal because it ated in various tissues, p70S6K 4EBP1 release + /Raptor pathway /Raptor causes a cohort of and attempt toc-Fos distin-P eIF4E systemic disorders— guish the ones that mTOR dyslipidemia, hyper- prolong health from Membrane docking/integration Membrane tension, cardiovascular the ones that mightCell proliferation Cell cycle arrest, pro-survival transcription www.sciencemag.org and translation autophagy and apoptosis disease, stroke, blind- diminish it. ness, kidney disease, Fig. 1. Regulation of insulin and IGF signaling. Insulin and IGF1 receptors form hybrids that BAX P References modulate the selectivity and affinity for insulin and insulin-like growth factors (IGF1 and IGF2). female infertility, and Met GSK-3β 1. M. Bliss,Met-tRNTheAi Discovery+ eIF2 P eIF2B P neurodegeneration. Insulin or IGF binding stimulates tyrosine autophosphorylation in the receptor ␤ subunits, which (active) activates the kinase and recruits cellular substrates—IRS1 and IRS2—for tyrosine phosphorylation. of Insulin (Univ. of ChicagoHSF1 Press, Chica- P Subtle genetic poly- Recruitment is regulated by serine phosphorylation of the IRS proteins, which inhibits the Hsp27 Tau n CREB P go, IL, 1982). morphism influenc- ERK-1 P (aggregate) interaction between its PTB domain and the phosphorylated receptor. Proinflammatory cytokines 2. M. Kasuga et al., Nature P es lifelong insulin increase the synthesis of SOCS1 or SOCS3, which promote ubiquitination and degradation of IRS1 298,667(1982).HSF1 PKC P I GLUT4 GSK-3β or I sensitivity, whereas and IRS2. Production of cAMP enhances expression of IRS2 through the activity of phosphorylated 3. P. Zimmet et al., Na- Downloaded from I vesicle (active) CREB. Tyrosine phosphorylation of IRS1 or IRS2 recruits and activates various SH2 domain– ture 414HSF1, 782P (2001). Akt P Neurotransmission distinct monogenic P 4. M. White, Insulin Signal- • Synaptic plasticity containing proteins, including the PI 3-kinase, which activates the PKB cascade. Abbreviations: pY, Pancreatic β-islet cells Hsp27 • Transmitter release Adipose, muscle and liver disorders are diffi- ing Pathway, Sci. STKE cerebellum, sensorimotor Insulin vesicles HSR phosphotyrosine; pS, phosphoserine; PKC␭/␨, protein kinase C ␭ or ␨; E2, ubiquitin conjugating (functional) cult to identify and (Connections Map, as and reuptake cortices, hippocampus, enzymes; TNF␣R, tumor necrosis factor–␣ receptor; GLP-1R, glucagon-like peptide–1 receptor; pituitary, hypothalamus seen November 2003), are usually associat- TRENDS in Pharmacological Sciences IL6R, interleukin-6 receptor; for other abbreviations, see the text. http://stke.sciencemag. ed with rare metabol- org/cgi/cm/cmp_12069.Figure 2. Insulin, IGF-I and IGF-II binding to IR and IGF-IR. Ligand binding triggers receptor autophosphorylation and RTK activation, permitting IRS-1, IRS-2 or Shc phosphorylation. Mitogenic signaling pursues via Grb2 activation of the GEF (guanine nucleotide exchange factor) SoS, enabling Ras/Rheb activation. Activated Ras/Rheb ic diseases. Acute and 5. F. Frasca et al., Mol. Cell. Biol.initiates19,3278 the MAPK/ERK (1999).pathway through Raf-1 phosphorylation and enhances mTOR/raptor signaling, collectively increasing cell growth, proliferation, protein expression and viability. Induction of the PI3K pathway enhances metabolic insulin effects and mitigates pro-apoptotic and anti-mitogenic signaling. Hsp90 client proteins are indicated chronic inflammation cause insulin resistance, IRS-protein complexes to mediate ubiquiti- 6. R. S. Savkur et. al., Nature Genet.with a29pink,bar 40and (2001).serve crucial roles in regulating insulin/IGF signaling. Potential modulation effects of insulin/IGF signaling components upon Hsp expression and 7. M. F. White et al., Nature 318function, 183 are (1985).shown in the black box. Abbreviations: BAD, Bcl-2-associated death promoter; BAX, Bcl-2-associated X; 4EBP1, eIF4E binding protein-1; CREB, cAMP-response which provides a frameworkInsulin to understand Signaling how nylation (19). in Ubiquitin-mediated Health degrada-and Disease Heatelement binding; eIF2, shockeukaryotic initiation factor response2; eIF4E, eukaryotic translation initiation factor-4E;andERK-1/2, extracellular-signal-regulatedinsulin-kinase-1/2; FoxO3a, forkhead 8. X. J. Sun et al., Nature 352, 73box (1991). ‘other’ 3a; GLUT4, glucose transporter 4; Grb2, growth factor receptor-bound protein 2; GSK-3b, glycogen synthase kinase-3b; HSF1, heat shock factor-1; Hsp, heat http://www.sbgn.org/ diet, physiological stress, and obesity promote tion of IRS1 and IRS2 might be a general shock protein; HSR, heat shock response; IGF-IR, insulin-like growth factor-I receptor; IR, insulin receptor; IRS-1/2, insulin receptor substrate-1/2; MAPK, mitogen-activated Met 9. M. Schubert et al., J. Neurosci.protein23, kinase; 7084MEK1, (2003).MAPK/ERK kinase 1; Met-tRNAi , initiator methionyl-tRNA; mTOR, mammalian target of rapamycin; raptor, regulatory-associated protein of mTOR; Science 302 (5651), 2003, 1710. associated neurodegeneration insulin resistance. Proinflammatory cytokines, mechanism of cytokine-induced insulin resis- 10. S. Ogg et al., Nature 389, 994MDM2, (1997).murine double minute-2; PDK1, phosphoinositide-dependent kinase-1; PI3K, phosphatidylinositol 3-kinase;