Fig. 1. Binding specificities of the EGF-related peptide growth factors. There are four categories of ligands that bind ErbB family receptors. EGF, AR and TGFα bind ErbB1; BTC, HB-EGF and EPR bind ErbB1 and ErbB4; NRG-1 and NRG-2 bind ErbB3 and ErbB4; and NRG-3 and NRG-4 bind ErbB4. See the text for more details.

Fig. 2. ErbB2 is the preferred dimerization partner for the other ErbB receptors. Ligand binding to ErbB1 (EGF), ErbB3 (NRG-1) or ErbB4 (NRG-1, BTC) induces the formation of receptor homodimers and ErbB2-containing heterodimers. ErbB3 homodimers do not signal (indicated by the X), since the receptor has impaired kinase activity. Only some of the possible ligand–receptor-induced combinations are indicated in the figure for the sake of simplicity.

Fig. 3. Specific phosphotyrosine residues and binding of signaling molecules to the ErbB RTKs. ErbB1: tyrosine residues that have been identified as autophosphorylation sites (Downward et al., 1984; Hsuan et al., 1989; Margolis et al., 1989; Walton et al., 1990) (in yellow) and sites for the Src kinase (Stover et al., 1995) (in black), including Y845 in the T loop of the kinase domain (shown by an asterisk) (Sato et al., 1995; Biscardi et al., 1999a), are indicated. Some of the proteins that have been shown to interact with specific tyrosine residues of ErbB1 are indicated: Shc binds via its PTB domain to Y1173 and Y1148, and via its SH2 domain to Y1173 (Batzer et al., 1994; Okabayashi et al., 1994; Sakaguchi et al., 1998); PLCγ binds to Y1173 (Chattopadhyay et al., 1999) and Y992 (Rotin et al., 1992); the major and minor binding sites for Grb2 are, respectively, Y1068 and Y1086 (Batzer et al., 1994; Okutani et al., 1994); Cbl binds Y1045 (Levkowitz et al., 1999); SHP1 binds to Y1173 (Keilhack et al., 1998). ErbB2: tyrosine residues that have been identified as autophosphorylation sites are indicated (Hazan et al., 1990; Segatto et al., 1990). Proteins that have been shown to interact with specific tyrosine residues are indicated: Shc binds via its PTB domain to Y1196 and Y1248, and via its SH2 domain to Y1248 and Y1221/2 (Ricci et al., 1995); the latter site has also been identified in Neu (Dankort et al., 1997); Grb2 binds Y1139 (Ricci et al., 1995) and the equivalent residue in Neu (Dankort et al., 1997); Chk binds Y1248 (Zrihan-Licht et al., 1998). ErbB3: phosphopeptide analyses of in vivo labeled ErbB3 have not been published. The p85 subunit of PI3K and the Shc binding sites have been mapped by phosphopeptide competition (Prigent and Gullick, 1994). Peptides encompassing Y1035 and Y1270 compete strongly, peptides encompassing Y1178, Y1203/05, Y1241 and Y1257 compete less strongly for p85 binding; a peptide encompassing Y1309 competes for Shc binding. The major and minor sites for Grb7 binding are, respectively, Y1180 and Y1243 (Fiddes et al., 1998). ErbB4: phosphopeptide analyses of in vivo labeled ErbB4 have not been published. Phosphopeptide competition analyses have shown that Shc binds Y1242 and Y1188 (Cohen et al., 1996b); the p85 subunit of PI3K binds Y1056 (Elenius et al., 1999). (Only the cytoplasmic domains of the four ErbB RTKS are shown; for graphic purposes, the receptors have not been aligned.)