The ErbB or Epidermal Growth Factor (EGF) family of receptor tyrosine kinases (RTKs) consists of four members: EGF R/ErbB1/HER1, ErbB2/Neu/HER2, ErbB3/HER3, and ErbB4/HER4. Under normal physiological conditions, the ErbB receptors play crucial roles in propagating signals regulating cell proliferation, differentiation, motility, and apoptosis. The ErbB proteins are not only important for the essential roles they play in normal developmental processes, but also for their association with human tumorigenesis.1
The ErbB family members are receptors for Neuregulins (NRGs) and EGF family growth factors. Upon ligand binding, ErbB receptors form homo- and heterodimers leading to the activation of their tyrosine kinase domain and subsequent autocatalytic phosphorylation of specific tyrosine residues in the cytoplasmic tail. ErbB2 and ErbB3 are unique family members.2 ErbB2 is an orphan receptor and requires heterodimer formation with a different ligand-bound family member to become activated. ErbB3 has an impaired kinase region due to a mutation in its catalytic domain and is tyrosine phosphorylated by other family members, most notably ErbB2. The NRG-driven ErbB2/ErbB3 heterodimer is the most potent and common ErbB receptor pairing.2
|Figure 1. EGF R is transactivated by several mechanisms involving crosstalk between different signaling systems. Examples include phosphorylation of EGF R by Jak downstream of the activated Growth Hormone Receptor. Additionally, intrinsic kinase activity may be stimulated through the release of membrane-associated EGF R ligand precursors following Wnt or GPCR agonist-mediated activation of metalloproteinases. [Note: figure adapted from Holbro, T. et al. (2003) Exp. Cell Res. 284:99.]|
Receptor transactivation or crosstalk between different classes of receptors has recently gained much interest. ErbB receptors can act as central signal integrators, propagating signals from many different sources. ErbB transactivation can be mediated by at least two general mechanisms. Either the ErbB receptors are phosphorylated by other kinases, or their intrinsic kinase activity is indirectly stimulated by other receptors (Figure 1).3 Integrins, cytokine receptors, G protein-coupled receptors (GPCRs), and voltage-gated Ca2+ channels can transactivate ErbB receptors through phosphorylation by other kinases.4 For example, the binding of Growth Hormone to its receptor activates the bound Janus-type Tyrosine Kinase (Jak), Jak2, which in turn phosphorylates tyrosine residues on EGF R. This provides an anchoring site for Grb2 and subsequent stimulation of the MAP Kinase pathway.5 By using siRNA silencing of Tyk2 and Jak1, Walters et al. show crosstalk between ErbB3 and the IFN-α signaling complex is also mediated by Jaks.6 Alternatively, GPCRs may promote the tyrosine phosphorylation of adaptor sites on ErbB receptors by activating other tyrosine kinases including Src.5
The EGF R can also be transactivated by the second mechanism, intrinsic kinase activation by other receptors. For instance, binding of GPCR agonists Endothelin, Thrombin, Bombesin, or Lysophosphatidic Acid rapidly stimulate activation of the metalloproteinase ADAM-10, cleaving the EGF R ligand precursor pro-HB-EGF.7,8 The soluble ligand is then able to activate the EGF R receptor in an autocrine/paracrine manner. EGF R may be activated in a similar manner by matrix metalloproteinase-mediated release of precursor ligands following stimulation by members of the Wnt family.9 Although the mechanisms are unclear, crosstalk has also been reported between other signaling systems including gp130, CCR3, PDGF receptors, TGF-ß, c-Met, and Ron.10-15
Crosstalk adds a new dimension to the complexity of signal transduction involving ErbB receptors. Further studies will continue to reveal the intricate molecular networks involving ErbB family members.