A new mechanism of receptor tyrosinesignaling and its role in brain development
Associate Chair, Department of Otolaryngology
Director, Kresge Hearing Research Institute
University of Michigan
Receptor Tyrosine Kinases (RTKs) form a family of transmembrane signalingmolecules that participate in many key cellular processes, including proliferation,survival, migration and differentiation. These receptors have long been thought toexert their biological effect through canonical RTK signaling. In this signalingmodality, ligand binding induces receptor dimerization, resulting in RTKtrans-phosphorylation that creates binding sites for adaptor proteins, which thenmediate activation of downstream soluble kinases that go on to phosphorylate targetssuch as transcription factors, which then alter transcription of their specific targetgenes. Studying ErbB4, a receptor for neuregulin-1 (NRG1) and other trophic factors,we and others discovered a novel mechanism for RTK function involving directnuclear signaling. In this alternate RTK pathway, ligand-induced activation of theErbB4-JMa isoform induces cleavage of the receptor, first by the tumor necrosisfactor-α-converting enzyme (TACE) in the extracellular juxtamembrane domain, thenby γ-secretase within the transmembrane domain. The ligand-induced cleavage ofErbB4 depends on its kinase activity. This sequence of events results in the releaseof the activated soluble intracellular domain (E4ICD), which translocates to thenucleus via a nuclear localization sequence. In this presentation, I will discuss ourfindings on the roles of direct nuclear signaling by ErbB4 in neural stem cells in theembryonic cerebral cortex, and it implications for astrogenesis and genomic stability.