ErbB

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.

[2] The ErbB protein family consists of 4 members v-ErbBs are homologous to EGFR, but lack sequences within the ligand binding ectodomain.

[4][9] The figure below shows the tridimensional structure of the ErbB family proteins, using the pdb files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4):[10][11][12][13] 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.

[18] Notably, the ErbB1 and ErbB4 are the two most studied and intact among the family of ErbB proteins, Which forms functional intracellular tyrosine kinases.

[17][18] 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.

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.

[27] Many breast tumors also have lower levels of PTEN, which is a lipid phosphatase that dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate, thereby reversing the action of PI3K.

[28] ErbB2 overexpression can occur in breast, ovarian, bladder, non-small-cell lung carcinoma, as well as several other tumor types.

[28] Trastuzumab targets tumor cells and causes apoptosis through the immune system by promoting antibody-dependent cellular cytotoxicity.

Research suggests that a low FISH test ratio in estrogen receptor positive breast cancers are less likely to respond to this drug.

Comparison of ErbB extracellular domain structures
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 .