Find ERBB4 Products Interaction Network for ERBB4 ERBB4 Details

Related Pathways Neuregulin Signaling View All Pathways

Synonyms: C-erb-b4, ERBB4, Erbb4 Cyt2, ERBB4 JM-A, HER4, MGC138404, p180erbB4

ErbB4 Pathway

ErbB4 (HER4) (p180erbB4) is a member of the EGF receptor tyrosine kinase (RTK) family that is activated by members of the neuregulin (neu) family (neuregulin differentiation factors, NDF); NRG1, NRG2, NRG3 and NRG4, and by some members of the EGF growth factor family; betacellulin (BTC), epiregulin (EREG) and heparin-binding EGF-like growth factor (HB-EGF). ErbB4 activation requires monomer dimerization and trans-phosphorylation of the cytoplasmic domains. ErbB4 can form homodimers (ErbB4:ErbB4) or heterodimers with ErbB1, ErbB2 or ErbB3. ErbB4 has been associated with processes of cell growth, survival, chemotaxis and differentiation. As a heterodimer with ErbB1 (HER1) or ErbB2 (HER2), ErbB4 can support cell transformation. ErbB4 has been linked to terminal differentiation within some tissues. The specific cell response is dependent upon the ligand, dimer, HER4 isoform and cell context.

The diverse functions of ErbB4 have been partially explained by the discovery that ErbB4 exists in at least four naturally occurring tissue-specific alternative mRNA splicing isoforms. One ErbB4 isoform pair varies in their extracellular juxtamembrane (JM) domains. These are designated as JM-a and JM-b. The ErbB4-JM-a isoform has been implicated as a regulator of cell differentiation. The JM-a isoform can be cleaved by the tumor necrosis factor-α converting enzyme (TACE) whereas, JM-b cannot. Cleavage at the level of the JM-domain causes the shedding (down-regulation) of the ErbB4 ectodomain along with its associated ligand. The ErbB4 receptor can be further cleaved by gamma-secretase. The resulting ErbB4 cytoplasmic product, S80, is a constitutively active protein kinase that regulates genes involved in the induction of differentiation such as STAT5. Another ErbB4 isoform pair varies in their cytoplasmic domains. They are designated as CYT-1 and CYT-2. ErbB4-CYT-1 contains a binding domain for phosphoinositide 3-kinas (PI3K). The PI3K signaling cascade is important for functions such as cell survival and protein synthesis. Activated ErbB4 dimers support cell growth and mitosis through activation of the p21Ras/Raf-1/MEK/ERK pathway.