We manually constructed a comprehensive pathway map for EGFR-mediated signaling () based on published scientific papers. The map includes EGFR endocytosis followed by its degradation or recycling, small guanosine triphosphatase (GTPase)-mediated signal transduction such as mitogen-activated protein kinase (MAPK) cascade, phosphatidylinositol polyphosphate (PIP) signaling, cell cycle, and G protein-coupled receptor (GPCR)-mediated EGFR transactivation via intracellular Ca2+
signaling. The map was created using CellDesigner (http://celldesigner.org/
), a software package that enables users to describe molecular interactions using a well-defined and consistent graphical notation (Funahashi et al, 2003
; Kitano, 2003
). The data of molecular interactions are stored in Systems Biology Markup Language (SBML; http://sbml.org/
) (Hucka et al, 2003
). Since SBML is a standard machine-readable model representation format, all the information can be used for a range of computational analysis, including computer simulation.
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 (more ...)
The map is based on the molecular interactions documented in 242 papers accessible from PubMed (see the list of references for EGFR Pathway Map). It comprises 211 reactions and 322 species. A 'species' is a term defined by SBML as 'an entity that takes part in reactions' and it is used to distinguish the different states that are caused by enzymatic modification, association, dissociation, and translocation.
The species shown on the EGFR map can be categorized as follows: 202 proteins, three ions, 21 simple molecules, 73 oligomers, seven genes, and seven RNAs. In the number of species, eight degraded products and one unknown molecule are also included. Among 202 protein species, we identified 122 molecules, among which are 10 ligands, 10 receptors, 61 enzymes (including 32 kinases), three ion channels, 10 transcription factors, six G protein subunits, and 22 adaptor proteins.
The reactions can be categorized as follows: 131 state transitions, 34 transportations, 32 associations, 11 dissociations, two truncations, and one unknown transition. Among these reactions, there are 247 interactions; these represent 206 catalyses, nine unknown catalyses, 16 inhibitions, 12 transcriptional activations, and four transcriptional inhibitions. There are clusters of reactions that are involved in specific functions, such as endocytosis, degradation, recycling of EGFR, small GTPase signaling, MAPK cascade, PIP signaling, cell cycle, Ca2+ signaling, and GPCR-mediated EGFR transactivation. Reactions within each cluster are visually collocated to improve readability of the map.