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Focus on HER ligands

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A receptor-ligand complex

Structure of a HER family receptor
These space-filling models show the extracellular domain of HER1/EGFR. At left, HER1 is shown by itself. At right, it is shown bound to epidermal growth factor (EGF), its associated ligand. Note that the binding of the ligand substantially changes the conformation of the receptor.1 Reproduced 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.

What is a ligand?

The general definition of a ligand is any molecule that binds to another molecule, particularly a smaller molecule that binds to a larger one to induce a biological effect.4

  • In the context of HER pathways, a ligand is a protein outside the cell that binds to the extracellular domain of a HER family receptor2
  • Not all ligands bind to all HER family receptors2
    • There are no known ligands that bind HER2
    • HER1/EGFR, HER3, and HER4 are each associated with one or more specific ligands
  • Normally, ligands are produced and are available to stimulate growth only when needed, such as during embryonic development1
  • Ligands such as growth factors are secreted by tumor cells in order to facilitate their growth and spread5

What effects does ligand binding have?

The binding of a ligand to a HER receptor is an early step in HER signaling pathways.

  • Ligand binding leads to a conformational change in the HER family receptor, as shown in the image above1
  • This change in receptor conformation allows the receptor to associate with another HER family receptor in a process called dimerization2
  • The intracellular tyrosine kinase domains of the dimerized receptors then become activated through transphosphorylation2
  • Activation of the tyrosine kinase domain induces multiple downstream cellular signals1,2
  • Downstream cellular signaling leads to numerous cellular effects1

In the next section, the steps of the receptor signaling process are given in greater detail.

 

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