page_title: ErbB
section_title: ErbB and Kinase activation
hierarchical_section_title: ErbB / ErbB and Kinase activation
caption_attribution_description: English: A superposition of similar interfaces observed in crystal structures of the ERBB kinases, including EGFR, ERBB2 (HER2) and ERBB4 (HER4). The cluster was identified by the ProtCID database. The protein chains are colored from blue to red from N to C terminus. The kinase at the top of each dimer activates the kinase at the bottom of each dimer, as identified by Zhang et al. (Cell v. 125, pp. 1137-1149, 2008). The image was made with PyMol.
context_page_description: The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor, its first discovered member. In humans, the family includes Her1, Her2, Her3, and Her4. The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.
  ErbB protein family signaling is important for development. For example, ErbB-2 and ErbB-4 knockout mice die at midgestation leads to deficient cardiac function associated with a lack of myocardial ventricular trabeculation and display abnormal development of the peripheral nervous system. In ErbB-3 receptor mutant mice, they have less severe defects in the heart and thus are able to survive longer throughout embryogenesis. Lack of Schwann cell maturation leads to degeneration of motor and sensory neurons.
context_section_description: 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. There are 11 growth factors that activate ErbB receptors.
  The ability ('+') or inability ('-') of each growth factor to activate each of the ErbB receptors is shown in the table below:
  The dimerization occurs after ligand bind to the extracellular domain of the ErbB monomers and monomer-monomer interaction establishes activating the activation loop in a kinase domain, that activates the further process of transphosphorylation of the specific tyrosine kinases in the kinase domain of ErbB's intracellular part. It is a complex process due to the domain specificity and nature of the members of ErbB family.  Notably, the ErbB1 and ErbB4 are the two most studied and intact among the family of ErbB proteins, Which forms functional intracellular tyrosine kinases. ErbB2 has no known binding ligand and absent of an active kinase domain in ErbB3 make this duo preferable to form heterodimers & share each other's active domains to activate transphosphorylation of the tyrosine kinases. The specific tyrosine molecules mainly trans or auto-phosphorylated are at the site Y992, Y1045, Y1068, Y1148, Y1173 in the tail region of the ErbB monomer. For the activation of kinase domain in the ErbB dimer, asymmetric kinase domain dimer of the two monomers is required with the intact asymmetric (N-C lobe) interface at the site of adjoining monomers. Activation of the tyrosine kinase domain leads to the activation of the whole range of downstream signaling pathways like PLCγ, ERK 1/2, p38 MAPK, PI3-K/Akt and more with the cell.
  When not bound to a ligand, the extracellular regions of ErbB1, ErbB3, and ErbB4 are found in a tethered conformation in which a 10-amino-acid-long dimerization arm is unable to mediate monomer-monomer interactions. In contrast, in ligand-bound ErbB-1 and unliganded ErbB-2, the dimerization arm becomes untethered and exposed at the receptor surface, making monomer-monomer interactions and dimerisation possible. The consequence of ectodomain dimerization is the positioning of two cytoplasmic domains 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 cytoplasmic domain of ErbB-1, that may become phosphorylated and in some cases de-phosphorylated (e.g., Tyr 992) upon receptor dimerization. Although a number of potential phosphorylation sites exist, upon dimerization only one or much more rarely two of these sites are phosphorylated at any one time.
caption: A superposition of similar interfaces observed in crystal structures of the ERBB kinases, including EGFR, ERBB2 (HER2) and ERBB4 (HER4). The protein chains are colored from blue to red from N to C terminus. The kinase at the top of each dimer (as shown) activates the kinase at the bottom of each dimer (Zhang et al., Cell v. 125, pp. 1137–1149, 2008). The cluster was identified with the ProtCID database. The image was made with PyMOL.
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