Heregulin-Induced Growth Factor Receptor Signaling and Breast Carcinogenesis

Neuregulin heregulin and betacellulin are two members of the epidermal growth factor EGF family of peptide growth factors. The receptors for these ligands are the erbB family of receptor protein tyrosine kinases. They include the EGF receptor, neu erB-2HER2,erb3HER3, and erbB-4HER4. Not only have neuregulin and betacellulin been implicated in mammary carcinogenesis, but deregulated signaling by the erbB family receptors are also thought to play a causative role in these processes. However, the interactions of neuregulin and betacellulin with the erbB family receptors have not been thoroughly characterized. Therefore, we have expressed the four erbB family receptors, singly and in pairwise combinations, in the BaF3 mouse pro- B-lymphocyte cell line. By stimulating the result in panel of cell lines with neuregulin, betacellulin or EGF and assaying receptor tyrosine phosphorylation, we have identified which erB family receptors are activated by these ligands. Furthermore, we have assessed ligand-induced coupling of receptors to cellular signaling pathways by measuring ligand stimulation of interleukin-3-independent growth in these cell lines. These data demonstrate that EGF, betacellulin, and neuregulin stimulate distinct patterns of erbB family receptor tyrosine phosphorylation and coupling to cellular signaling pathways. These differences may account for their different biological activities.