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. 2005:1:2005.0010.
doi: 10.1038/msb4100014. Epub 2005 May 25.

A comprehensive pathway map of epidermal growth factor receptor signaling

Affiliations

A comprehensive pathway map of epidermal growth factor receptor signaling

Kanae Oda et al. Mol Syst Biol. 2005.

Abstract

The epidermal growth factor receptor (EGFR) signaling pathway is one of the most important pathways that regulate growth, survival, proliferation, and differentiation in mammalian cells. Reflecting this importance, it is one of the best-investigated signaling systems, both experimentally and computationally, and several computational models have been developed for dynamic analysis. A map of molecular interactions of the EGFR signaling system is a valuable resource for research in this area. In this paper, we present a comprehensive pathway map of EGFR signaling and other related pathways. The map reveals that the overall architecture of the pathway is a bow-tie (or hourglass) structure with several feedback loops. The map is created using CellDesigner software that enables us to graphically represent interactions using a well-defined and consistent graphical notation, and to store it in Systems Biology Markup Language (SBML).

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Figures

Figure 1
Figure 1
EGFR Pathway Map. This map was created using CellDesigner ver. 2.0 (http://www.systems-biology.org/002/). A total of 219 reactions and 322 species were included. The map can be best viewed in the PDF format. Abi, abl-interactor; ADAM, a disintegrin and metalloproteinase; ADPR, ADP-ribose; Akt, v-akt murine thymoma viral oncogene homolog; AP-1, activator protein-1; Bad, BCL2-antagonist of cell death; cADPR, cyclic ADP-ribose; CAK, cyclin-dependent kinase-activating kinase; CaM, calmodulin; CaMK, calcium/calmodulin-dependent protein kinase; c-Cbl, Casitas B-lineage lymphoma proto-oncogene; CD, cluster of differentiation; Cdc, cell division cycle; Cdk, cyclin-dependent kinase; c-Fos, v-fos FBJ murine osteosarcoma viral oncogene; Chk, c-src tyrosine kinase (Csk) homologous kinase; c-Jun, v-jun sarcoma virus 17 oncogene homolog; c-Myc, v-myc myelocytomatosis viral oncogene homolog; CREB, cAMP response element-binding protein; c-Src, v-src sarcoma viral oncogene homolog; cyt., cytosol; DAG, diacylglycerol; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Elk, Ets-like protein; end., endosome; EP, prostaglandin E receptor; Eps, EGF receptor pathway substrate; ER, endoplasmic reticulum; ErbB, erythroblastic leukemia viral (v-erb-b) oncogene homolog; ERK, extracellular signal-regulated kinase; Gab, GRB2-associated binding protein; GPCR, G protein-coupled receptor; Grb, growth factor receptor-bound protein; HB-EGF, heparin-binding EGF-like growth factor; IP3R, inositol 1,4,5-triphosphate receptor; IP3, inositol 1,4,5-triphosphate; JNK, c-Jun N-terminal kinase; KDI, kinase domain I; LARG, leukemia-associated rho guanine nucleotide exchange factor; LIMK, LIM (Lin-11 Isl-1 Mec-3) kinase; LPA, lysophosphatidic acid; LPA1/2, lysophosphatidic acid G protein-coupled receptor 1/2; lyso., lysosome; m., messenger; MAPK, mitogen-activated protein kinase; MEKK, MAPK/ERK kinase kinase; MKK, MAP kinase kinase; MKP, MAP kinase phosphatase; MLK, mixed lineage kinase; NAD, nicotinamide adenine dinucleotide; nuc., nucleus; PAK1, p21/Cdc42/Rac1-activated kinase; PDK, 3-phosphoinositide-dependent protein kinase; PGE2, prostaglandin E2; Pi, phosphoric ion; PI3,4,5-P3, phosphatidylinositol-3,4,5-triphosphate; PI3,4-P2, phosphatidylinositol-3,4-bisphosphate; PI3K, phosphatidylinositol-3-kinase; PI4,5-P2, phosphatidylinositol-4,5-bisphosphate; PI4-P, phosphatidylinositol-4-phosphate; PI5K, phosphatidylinositol-5-kinase; PIP, phosphatidylinositol polyphosphate; PKB, protein kinase B; PKC, protein kinase C; pl.m., plasma membrane; PLC, phospholipase C; PLD, phospholipase D; PP, protein phosphatase; PTB, phosphotyrosine-binding domain; PTEN, phosphatase and tensin homolog; Pyk, proline-rich tyrosine kinase; Rab5a, RAS-associated protein RAB5a; Raf, v-raf-1 murine leukemia viral oncogene homolog; Ras, rat sarcoma viral oncogene homolog; RasGAP, Ras GTPase-activating protein; Rb, retinoblastoma; RGS, regulator of G-protein signaling; Rin, Ras interaction; RN-tre, related to the N-terminus of tre; RSK, ribosomal protein S6 kinase; RYR, ryanodine receptor; S, serine; S1P, sphingosine-1-phosphate; S1P1/2/3, sphingolipid G protein-coupled receptor 1/2/3; SERCA, sarcoplasmic/endoplasmic reticulum calcium ATPase; Shc, Src homology 2 domain containing transforming protein; SHP, Shp-2 tyrosine phosphatase; SOS, son of sevenless homolog; SPRY, Sprouty; STAT, signal transducer and activator of transcription; T, threonine; TGFα, transforming growth factor alpha; Ubc, ubiquitin-conjugating enzyme; Y, tyrosine. This image is also available as high resolution PDF (see Supplementary PDF 1) or Scalable Vector Graphic (SVG) or SBML (see Supplementary SBML 1).
Figure 2
Figure 2
The bow-tie architecture of the EGFR signaling pathway. A simplified diagram was created based on the EGFR signaling map in Figure 1. Arrows in this figure represent an informal notation of 'flow of reaction'. Various ligands bind to diverse receptor heterodimers, which then converge into a handful of molecules building a conserved core. Activities of these molecules play important roles in controlling diverse responses. Notable interactions are color-coded: red, positive feedback loop; blue, negative feedback loop; purple, inhibitory feed-forward path; green, crosstalk from GPCR cascade to EGFR cascade via calcium release. This image is also available as high resolution PDF (see Supplementary PDF 2) or Scalable Vector Graphic (SVG).
Figure 3
Figure 3
Main symbols adopted by CellDesigner ver. 2.1.1. These symbols are provided in CellDesigner ver. 2.1.1. Size and color of each module are configurable. CellDesigner also provides X-Y coordinates for each module and can distinguish between cellular compartments.
Figure 4
Figure 4
Expression of the inner structures and states. The active state of the molecule is indicated by a dashed line surrounding the molecule. State changes of a component such as phosphorylation, acetylation, ubiquitination, and allosteric changes can be represented with specific information such as target residue and position.
Figure 5
Figure 5
Ellipsis in drawing association states of proteins using an 'address'. (A) Precise association states between EGFR and adaptors. Three adaptor proteins, Shc, Grb2, and Gab1, bind to the activated EGFR via its autophosphorylated tyrosine residues. Shc binds to activated EGFR and is phosphorylated on its tyrosine 317. Grb2 binds to activated EGFR either directly or via Shc bound to activated EGFR. Gab1 also binds to activated EGFR either directly or via Grb2 bound to activated EGFR, and is phosphorylated on its tyrosine 446, 472, and 589. (B) The same signaling pathway as in panel A using an 'address' such as 'Grb2@EGFR.Y1068/1086P', thereby achieving a presentation of the pathway details. EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Gab, GRB2-associated binding protein; Grb, growth factor receptor-bound protein; Shc, Src homology 2 domain containing transforming protein.
Figure 6
Figure 6
Combinations of multiple states of complexes. (A) Omitted notation in the EGFR Pathway Map. The 85 kDa regulatory subunit of phosphatidylinositol 3-kinase (PI3K (p85)) binds to active ErbB3 receptor via its phosphorylated tyrosine residues: Tyr1035, Tyr1178, Tyr1203/05, Tyr1241, Tyr1257, and Tyr1270. (B) Detailed portrayal of panel A for distinguishing the complexes according to differences of phosphotyrosine residues. ErbB3, erythroblastic leukemia viral (v-erb-b) oncogene homolog 3; PI3K (p85), 85 kDa regulatory subunit of phosphatidylinositol 3-kinase.

Comment in

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