The ErbB receptor tyrosine kinases comprise the four members, epidermal growth factor receptor (EGFR)/ErbB1, Her2/ErbB2, ErbB3 and ErbB4. ErbB-family members are known to play critical roles in regulating cell proliferation, differentiation, apoptosis and migration. ErbB4 (Erythroblastic Leukemia Viral Oncogene Homolog-4) is a 180-kDa transmembrane RTK (Receptor Tyrosine Kinase) that responds to many different ligands, including neuregulin 1 (heregulin), neuregulin 2, neuregulin 3, neuregulin 4, betacellulin, epiregulin, and heparin-binding EGF-like growth factor . ErbB4 is known to have a unique signaling feature among the ErbB-family members. Stimulation with Nrg-1, a ligand of ErbB4, not only activates downstream signaling molecules close to or on the cytoplasmic face of the plasma membrane but also cleaves the ErbB4 extracellular domain and the intracellular domain by TNF-alpha-converting enzyme (TACE) and Gamma-secretase, respectively. Cleavage by TACE removes the extracellular domain and leaves the membrane-associated 80-kDa ErbB4 fragment (m80 ErbB4). The m80 ErbB4 fragment is further cleaved by Gamma-secretase to release the soluble 80-kDa ErbB4 fragment, termed the ErbB4 intracellular domain (4ICD), into the cytoplasm. Then, 4ICD acts as a non-receptor-type tyrosine kinase and can shuttle between the cytoplasm and the nucleus. 4ICD can signal directly to the nucleus to regulate transcription (Ref.1 and 2).
ErbB4 contains an extracellular ligand-binding domain, a hydrophobic transmembrane domain, an intracellular tyrosine kinase domain, and carboxyl-terminal tyrosine residues that serve as sites of phosphorylation. Ligand binding to ErbB4 stimulates ErbB4 homodimerization or heterodimerization of ErbB4 with another ErbB receptor. Dimerization enables ErbB4 transphosphorylation on tyrosine residues and coupling of the phosphorylated tyrosine residues to signaling effectors and biological responses (Ref.3).Activation of ErbB4 can trigger conventional intracellular signal transduction pathways such as the PI3K/Akt and Ras/MAPKs cascades, or can lead to interactions with WW domain-containing proteins, such as tumor suppressor WW domain-containing oxidoreductase (WWOX) and ubiquitin ligases through three intracellular PPXY motifs. The PI3K/Akt and PI3K/Akt and Ras/MAPKs signaling pathways probably mediate the survival effect of NRG. NRG induces prolonged activation of PKB/Akt and ERK(Ref.4).
ErbB2 (HER2/Neu), another ErbB family receptor tyrosine kinase, may be responsible for the fact that ErbB4 possesses tumor suppressor and oncogenic activities. Ligand-binding to ErbB4 and dimerization with ErbB2 leads to signal transduction through the transmembrane helixes and activation of the intracellular kinase domain, leading to tyrosine phosphorylation. The phosphorylated intracellular domains then recruit signaling proteins containing phosphotyrosine-binding and Src homology-2 domains. Phosphatidylinositol 3-kinase (PI3K), Src, and ShcA are important effector molecules of ErbB2/ErbB4 signaling. These proteins relay the signal to downstream signaling pathways, which regulate a variety of cell-specific functions, including differentiation, proliferation, and cell migration (Ref.5).ErbB4 is widely expressed in many tissues at the mRNA level, including the epithelial lining of the gastrointestinal and respiratory tracts as well as urinary, reproductive, skin, skeletal muscle, circulatory, endocrine, and nervous system tissues. The highest expression levels of ErbB4 receptor during development are observed in the brain and heart. ErbB4 plays an essential role in alveoli maturation during pregnancy-induced epithelial differentiation and during the initiation of lactation at parturition in breast tissue. ErbB4 is also essential for both cardiac muscle differentiation and axon guidance in the central nervous system (Ref.2).