ERBB TYROSINE KINASES AND THE 2 NEUREGULIN FAMILIES CONSTITUTE A LIGAND-RECEPTOR NETWORK

The recently isolated second family of neuregulins, NRG2, shares its p rimary receptors, ErbB-3 and ErbB-4, and induction of mammary cell dif ferentiation with NRG1 isoforms, suggesting functional redundancy of t he two growth factor families. To address this possibility, we analyze d receptor specificity of NRGs by using an engineered cellular system. The activity of isoform-specific but partly overlapping patterns of s pecificities that collectively activate all eight ligand-stimulatable ErbB dimers was revealed. Specifically, NRG2-beta, like NRG1-alpha, em erges as a narrow-specificity ligand, whereas NRG2-alpha is a pan-ErbB ligand that binds with different affinities to all receptor combinati ons, including those containing ErbB-1, but excluding homodimers of Er bB-2. The latter protein, however, displayed cooperativity with the di rect NRG receptors. Apparently, signaling by all NRGs is funneled thro ugh the mitogen-activated protein kinase (MAPK). However, the duration and potency of MAPK activation depend on the identity of the stimulat ory ligand-receptor ternary complex. We conclude that the NRG-ErbB net work represents a complex and nonredundant machinery developed for fin e-tuning of signal transduction.