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Focus on receptor activation
Slide Deck
View the HER Pathways Overview slide deck
Activation of HER receptors has numerous cellular effects and is a complex process
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.6 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.
Receptor activation is a complex, multistep process
In order to convert extracellular signals into intracellular signals, HER family receptors must be activated, a process involving multiple steps:
- First, a HER family receptor binds its associated ligand1
- Upon ligand binding, the conformation of the receptor changes from closed to open1
- HER2, which does not bind a ligand, exists in the open conformation
- A HER family receptor in the open conformation is available for dimerization, or pairing with another HER family receptor1
- Receptor dimerization is necessary in order to activate downstream signaling pathways6
- Because HER2 exists in an open conformation, it is continuously available for dimerization1
- After dimerization, receptors are in close proximity to one another and can thus transactivate one another2
- In transactivation, the intracellular tyrosine kinase domains of the 2 receptors are phosphorylated3
- Transactivation induces the recruitment and activation of downstream cellular signaling proteins, which have numerous effects on the cell3
Receptor regulation through internalization
Prolonged HER pathway signaling produces detrimental effects on cells. A complex system of regulation is required in order to keep signaling pathways turned off when not needed. Receptor internalization is a key component of this process1:
- When ligand-receptor complexes are formed, they may cluster together on the cell surface1
- These clusters form pits that bud off into endosomes, which sequester their contents from the rest of the cell1
- Within the endosome, 1 of 2 processes may occur1
- The ligand may dissociate from the HER family receptor, which is then recycled back to the surface of the cell
- The receptor may be targeted for destruction, so that it is unable to signal further
Receptor internalization
In this image, HER family receptors are shown being internalized into endosomes, enclosed structures that sequester their contents from the rest of the cell. Endosomes then recycle receptors back to the surface of the cell or target receptors for destruction. This process is an important regulator of HER family signaling in normal cells, and is retained in cancerous cells.1 Adapted with permission from Lippincott Williams & Wilkins. 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.
