Combinatorial complexity is a feature of ERBB receptor signaling. (A) Diagram depicting a selected subset of interactions of epidermal growth factor (EGF), EGF receptor (EGFR), heregulin (HRG), ERBB3, GRB2, SOS1, GAB1, SHC1, and PI3K considered in the model. These binding partners of EGFR and ERBB3 are documented in NetPath and HPRD. This diagram also depicts substrates of the EGFR kinase domain (six tyrosine residues in EGFR and seven tyrosine residues in ERBB3). These sites of phosphorylation in EGFR and ERBB3 are documented in HPRD and Phospho. ELM. Next to each component of EGFR and ERBB3, the number of possible component states is indicated. These counts are based only on the proteins, sites of phosphorylation, and interactions depicted in this diagram. Note that additional interactions are considered in the model (cf. Figure2). For example, in this diagram, we do not consider phosphorylation of SOS1 and GAB1. Ligand binding sites have two possible states (see below). Docking sites for SHC1 (blue rectangles) have eight possible states (see below). Docking sites for GRB2 (green rectangles) have six possible states. In the model, Y1114 in EGFR (white rectangle) is a docking site for both GRB2 and SHC1. Thus, this docking site has 12 possible states. Docking sites for PI3K (cyan rectangles) have three possible states. Based on these counts of possible component states, the number of possible states for an EGFR monomer is 2·8·6·8·12·6·6 = 331,776, and the number of possible states for an ERBB3 monomer is 2·36·8 = 11,664. An EGFR: ERBB3 heterodimer has more than 3.8 × 109 states, and an EGFR homodimer has more than 5.5 × 1010 states. When we consider the additional interactions included in the model but not shown here, we find that the number of possible states for an EGFR homodimer is much greater than a googol (10100). (B) As illustrated in this panel, the ectodomain of EGFR has two possible ligand-bound states: free or bound to EGF. (C) As illustrated in this panel, a docking site in EGFR for SHC1 has eight possible states: unphosphorylated, phosphorylated, bound to unphosphorylated SHC1, bound to phosphorylated SHC1, bound to SHC1 in complex with GRB2, bound to SHC1 in complex with GRB2: SOS1, bound to SHC1 in complex with GRB2: GAB1, and bound to SHC1 in complex with a ternary complex of GRB2, SOS1, and GAB1.