Members
ERBB1 | ERBB2 | ERBB3 | ERBB4 |
Controlled levels of signaling through ERBBs and other growth factor receptors are maintained by keeping a relatively limited amount of receptors at the cell surface.
ERBBs receptors overexpression can lead to disease states such as the genesis or progression of tumors. Hence, mechanisms must exist for localizing and maintaining a precise concentration of growth factor receptors at the site of signal reception.
ERBB2, ERBB3, and ERBB4 are somewhat unique among studied receptor tyrosine kinases in that they exhibit impaired ligand-induced internalization, down-regulation, and degredation. Infact the rate of degredation is dependent on factors that appear to act independent of ligand binding.
Nrdp-1 (Neuroregulin receptor degradation protein-1) is one such protein. Ndrp-1 is an E3 ubiqitin ligase that tags ErbB3 for degredation in non-lysosomal compartments. The cycling of ErbB1 is similar to that of EGF receptor and is included for contrast. The EGFR cycling is illustrated on the CBL Pathway.
The neuregulins bind to ERBB3 or ERBB4 and can activate the ERBB2 receptor through a heterodimerization mechanism not shown in this illustration. Heterodimers of ERBB3 and ERBB2, which has no direct ligand, are potent in causing cell transformation.
Structure and activation of HER proteins
The extracellular regions of HER proteins are composed of four domains, numbered I, II, III and IV. Domains I and III are ligand-binding domains, whereas domains II and IV are cysteine-rich domains that bind to each other and other receptors.
The tyrosine-kinase domain has two lobes that are shared among the tyrosine-kinase family and are termed the N-terminal and C-terminal lobes.
The C-terminal tail contains many tyrosines, which are targets for phosphorylation. When not liganded, the ECD is folded into a closed conformation owing to an intramolecular interaction between domains II and IV (see inactive monomer).
The HER ligand binds to domains I and III, bringing them together. The result is a refolding that exposes domain II, which is the dimerization interface.
The dimerization domains of two active receptors interact, bringing the intracellular domains into close proximity and the interaction of the two kinase domains results in transphosphorylation.
Pathology
ERBB receptor tyrosine kinases have important roles in human cancer. In particular, the expression or activation of epidermal growth factor receptor EGFR and ERBB2 are altered in many epithelial tumours.
See also
References
Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005 May;5(5):341-54. PMID: 15864276
de Bono JS, Rowinsky EK. The ErbB receptor family: a therapeutic target for cancer. Trends Mol Med. 2002;8(4 Suppl):S19-26. PMID: 11927283