A discrete three-amino acid segment (LVI) at the C-terminal end of kinase-impaired ErbB3 is required for transactivation of ErbB2

ErbB3 is unique among other members of the receptor tyrosine kinase family of growth factor receptors in that its kinase domain is enzymatically impai red. This renders it incapable of transducing a signal in response to ligan d binding. However, in conjunction with ErbB2, ErbB3 is a potent mediator o f signaling by the growth factor heregulin. Heregulin binding to ErbB3 indu ces formation of a heterodimeric complex with ErbB2, and this results in tr ansactivation of the ErbB2 kinase. Although interaction between the extrace llular domains of these receptors is an essential part of this process, it was not clear whether interaction between the cytoplasmic domains is also n ecessary for transactivation. By examining the abilities of a series of cyt oplasmic domain mutants of ErbE3 to activate ErbB2, we have found a discret e sequence of three amino acid residues (LVI), located at the carboxyl-term inal end of the impaired ErbB3 kinase region, that is obligatory for transa ctivation. We conclude that formation of a functional ErbB2-ErbB3 signaling complex requires the presence of a specific structural feature within the ErbB3 cytoplasmic domain and suggest that ErbB2 transactivation results fro m a physical interaction between the cytoplasmic domains of these receptors .