ErbB/HER Signaling

The ErbB receptor tyrosine kinase family consists of four cell surface receptors: ErbB1/ EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. ErbB receptors are typical cell membrane receptor tyrosine kinases that are activated following ligand binding and receptor dimerization. Ligands can either display receptor specificity (i.e. EGF, TGF-α, AR, and Epigen bind EGFR) or bind to one or more related receptors; neuregulins 1–4 bind ErbB3 and ErbB4 while HB-EGF, epiregulin, and β-cellulin activate EGFR and ErbB4. ErbB2 lacks a known ligand, but recent structural studies suggest its structure resembles a ligand-activated state and favors dimerization.

The ErbB receptors signal through Akt, MAPK, and many other pathways to regulate cell proliferation, migration, differentiation, apoptosis, and cell motility. ErbB family members and some of their ligands are often over-expressed, amplified, or mutated in many forms of cancer, making them important therapeutic targets. For example, researchers have found EGFR to be amplified and/or mutated in gliomas and NSCLC while ErbB2 amplifications are seen in breast, ovarian, bladder, NSCLC, as well as several other tumor types. Preclinical and clinical studies have shown that dual targeting of ErbB receptors display better efficacy than single treatment.

Besides functioning as receptors on the cell surface, ErbB family proteins are also present in the nucleus to act as both kinases and transcriptional regulators. For example, EGFR could be transported into the nucleus where it functions as a tyrosine kinase to phosphorylate and stabilize PCNA. Similarly, membrane-bound ErbB2 interacts with importin β1 and Nup358 and migrates to the nucleus via endocytic vesicles. Inside the nucleus, ErbB2 modulates the transcription of multiple downstream genes including COX-2. In addition, NRG or TPA stimulation promotes ErbB4 cleavage by γ-secretase, releasing an 80 kDa intracellular domain that translocates to the nucleus to induce differentiation or apoptosis. Upon activation and cleavage, ErbB4 can also form a complex with TAB2 and N-CoR to repress gene expression.

Signaling through ErbB networks is modulated through dense positive and negative feedback and feed forward loops, including transcription-independent early loops and late loops mediated by newly synthesized proteins and miRNAs. For example, activated receptors can be switched “off” through dephosphorylation, receptor ubiquitination, or removal of active receptors from the cell surface through endosomal sorting and lysosomal degradation.

Selected Reviews:

• Arteaga CL, Engelman JA (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25(3), 282–303.
• Avraham R, Yarden Y (2011) Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat. Rev. Mol. Cell Biol. 12(2), 104–17.
• Baselga J, Swain SM (2009) Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat. Rev. Cancer 9(7), 463–75.
• Ferrer-Soler L, Vazquez-Martin A, Brunet J, Menendez JA, De Llorens R, Colomer R (2007) An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: Gefitinib (Iressa) -induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review). Int. J. Mol. Med. 20(1), 3–10.
• Moasser MM (2007) The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26(45), 6469–87.
• Tebbutt N, Pedersen MW, Johns TG (2013) Targeting the ERBB family in cancer: couples therapy. Nat. Rev. Cancer 13(9), 663–73.
• Yarden Y, Pines G (2012) The ERBB network: at last, cancer therapy meets systems biology. Nat. Rev. Cancer 12(8), 553–63.
• Yarden Y, Shilo BZ (2007) SnapShot: EGFR signaling pathway. Cell 131(5), 1018.

We would like to thank Dr. Jinyan Du, Merrimack Pharmaceuticals Inc., Cambridge, MA, for contributing to this diagram.

created October 2004

revised September 2016