ErbB proteins are type I transmembrane receptor tyrosine kinases

ErbB proteins are type I transmembrane receptor tyrosine kinases. Each has an extracellular region containing two extracellular cysteine-rich domains, a transmembrane domain, a short intracellular juxtamembrane region, a tyrosine kinase domain and a carboxy-terminal tail. In response to neuregulin 1 (NRG1) stimulation, ErbB proteins become dimerized to form homo- and heterodimers, such as ErbB2–ErbB3, ErbB4–ErbB4, ErbB2–ErbB4 and ErbB4–epidermal growth factor receptor (EGFR). ErbB2 does not bind to NRG1 (indicated by the black crosses) but has an active kinase domain; ErbB3 binds to NRG1 but has an impaired tyrosine kinase domain (indicated by the purple cross). Therefore, ErbB2 and ErbB3 need to form heterodimers with each other or with ErbB4 to be functional, whereas ErbB4 homodimers can bind to NRG1 and become activated. Activation of the tyrosine kinase domains leads to auto- and trans-phosphorylation of the intracellular domains, generating docking sites for the adaptor proteins Grb2 and Shc, which activate the Raf–MEK–ERK pathway, and for the p85 subunit of PI3K (indicated in the figure for the ErbB2–ErbB3 heterodimer), which activates the PI3K pathway and subsequently mTOR-dependent protein synthesis. NRG1 activates CDK5, which is also stimulated by neuronal activity. EGFR does not bind to NRG1. Its downstream pathways include ones that involve JNK, Src, Abl, and PKC in addition to ones that involve ERK and PI3K/Akt.

Publication

Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. () Lin Mei, et al. Nat Rev Neurosci. ;9(6):437-452. Figure: F2. Homo sapiens

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