Growth factor-specific signaling pathway stimulation and gene expression mediated by ErbB receptors

The mechanisms by which receptor tyrosine kinases (RTKs) utilize intracellu lar signaling pathways to direct gene expression and cellular response rema in unclear. A current question is whether different RTKs within a single ce ll target similar or different sets of genes. In this study we have used th e ErbB receptor network to explore the relationship between RTK activation and gene expression, We profiled growth factor-stimulated signaling pathway usage and broad gene expression patterns in two human mammary tumor cell l ines expressing different complements of ErbB receptors. Although the growt h factors epidermal growth factor (EGF) and neuregulin (NRG) 1 similarly st imulated Erk1/2 in MDA-MB-361 cells, EGF acting through an EGF receptor/ Er bB2 heterodimer preferentially stimulated protein kinase C, and NRG1 beta a cting through an ErbB2/ErbB3 heterodimer preferentially stimulated Akt, The two growth factors regulated partially overlapping yet distinct sets of ge nes in these cells. In MDA-MB-453 cells, NRG1 beta acting through an ErbB2/ ErbB3 heterodimer stimulated prolonged signaling of all pathways examined r elative to NRG2 beta acting through the same heterodimeric receptor species , Surprisingly, NRG1 beta and NRG2 beta also regulated partially overlappin g but distinct sets of genes in these cells. These results demonstrate that the activation of different RTKs, or activation of the same RTKs with diff erent Iigands, can lead to distinct profiles of gene regulation within a si ngle cell type. Our observations also suggest that the identity and kinetic s of signaling pathway usage by RTKs may play a role in the selection of re gulated genes.