ErbB

The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease.^[1] In mice loss of signaling by any member of the ErbB family results in embryonic lethality with defects in organs including the lungs, skin, heart and brain. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor. ErbB-1 and ErbB-2 are found in many human cancers and their excessive signaling may be critical factors in the development and malignancy of these tumors.^[2]

Family members

The ErbB protein family consists of 4 members

• ErbB-1, also named epidermal growth factor receptor (EGFR)
• ErbB-2, also named HER2 in humans and neu in rodents
• ErbB-3, also named HER3 and
• ErbB-4, also named HER4

Structure

ErbB receptors are made up of an extracellular region or ectodomain that contains approximately 620 amino acids, a single transmembrane spanning region and a cytoplasmic tyrosine kinase domain. The extracellular region of each family member is made up of four subdomains, L1, CR1, L2 and CR2, were "L" signifies a leucine-rich repeat domain and "CR" a cysteine-rich region. These subdomains are shown in blue (L1), green (CR1), yellow (L2) and red (CR2) in the figure below. These subdomains are also referred to as domains I-IV respectively.^[3][4] The figure below was created using the pdb files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4).^[2][5][6][7]

Comparison of ErbB extracellular domain structures

Kinase activation

The four members of the ErbB protein family are capable of forming homodimers, heterodimers, and possibly higher order oligomers upon activation by a subset of potential growth factor ligands.^[3] There are 11 growth factors that activate ErbB receptors. The ability of each growth factor to activate each of the ErbB receptors is shown in the table below, + and - signifying ability and inability to activate each of the ErbB receptors respectively.^[8]

When not bound to a ligand the extracellular regions of ErbB-1, -3 and -4 are found in a 'tethered' conformation in which a 10 amino acid long dimerisation arm is unable to mediate monomer-monomer interactions. In contrast, in ligand bound ErbB-1 and unliganded ErbB-2 the dimerisation arm becomes untethered and exposed at the receptor surface making monomer-monomer interactions and dimerisation possible.^[8] The consequence of ectodomain dimerisation is the positioning of two cytoplasmic domain such that transphosphorylation of specific tyrosine, serine and threonine amino acids can occur within the cytoplasmic domain of each ErbB. At least 10 specific tyrosines, 7 serines and 2 threonines have been identified within the cytoplamic domain of ErbB-1, that may become phosphorylated and in some cases de-phosphorylated (e.g. Tyr 992) upon receptor dimerisation.^[9][10][11] Although a number of potential phosphorylation sites exist, upon dimerisation only one or much more rarely two of these sites are phosphorylated at any one time.^[9]

Role in cancer

ErbB-1 is overexpressed in many cancers. Drugs such as cetuximab, gefitinib, erlotinib are used to inhibit it. It has recently been shown that acquired resistance to the two first can be linked to hyperactivity of ErbB-3.^[12] This is linked to an acquired overexpression of c-MET which phosphorylates ErbB-3, which in turn activates the Akt pathway.^[13] ErbB-2 (HER-2) is often overexpressed in breast cancer. The drug Trastuzumab (Herceptin) targets this receptor. Only one third of the women respond to Trastuzumab, currently it is not known what causes the resistance to Trastuzumab.

References