HER Signaling

The HER family of receptors

Cellular receptors are responsible for translating signals from outside the cell into signals within the cell. These signals have numerous effects (such as growth, proliferation, and survival), and receptor activation is tightly regulated in normal cells.1

The HER family consists of 4 structurally related cellular receptors, which interact in many ways.2 They include HER1 (EGFR), HER2, HER3, and HER4. HER1/EGFR, HER3, and HER4 are each associated with one or more specific ligands, whereas there are no known ligands that bind HER2.3,4

Structure of HER family receptors

HER receptor structure image showing ligand binding region, dimerization domain, and tyrosine kinase domain

HER receptor activation

Receptor activation is a multistep process. After ligand binding, receptors dimerize, or form pairs.1 Upon dimerization, the intracellular tyrosine kinase domains of the receptors are phosphorylated, activating the receptors and initiating downstream signaling cascades, such as the MAPK proliferation pathway and/or the PI3K/Akt prosurvival pathway.4

With 4 members of the HER family of receptors, each of which is able to homodimerize or to heterodimerize with other members of the HER family, multiple receptor combinations are possible.1 HER2 is the preferred dimerization partner for all members of the HER receptor family since it exists in an open conformation and is continually available for dimerization.1,4,5

HER receptor activation image showing MAPK and PI3K

This diagram illustrates the effects of HER receptor dimerization and subsequent activation. After ligand binding, receptors dimerize, or form pairs. Upon dimerization, the intracellular tyrosine kinase domains of the receptors are phosphorylated, activating the receptors and initiating downstream signaling.4 Role of HER2 gene expression in breast carcinoma. Ménard S, Tagliabue E, Campiglio M, Pupa SM. Copyright © 2000 J Cell Phys. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

References

  1. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426.
  2. Burgess AW, Cho HS, Elgenbrot C, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell. 2003;12:541-542. PMID: 14527402
  3. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159-3167. PMID: 10880430
  4. Ménard S, Tagliabue E, Campiglio M, Pupa SM. Role of HER2 gene overexpression in breast carcinoma. J Cell Physiol. 2000;281:150-162. PMID: 10623878
  5. Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997;16:1647-1655. PMID: 9130710