ErbB2-ErbB3 Heterodimers

The ErbB (Erythroblastic Leukemia Viral Oncogene Homolog) family of transmembrane RTKs (Receptor Tyrosine Kinases) plays an important role in the pathogenesis of many cancers (Ref.1). This family is comprised of four members EGFR (Epidermal Growth Factor Receptor), ErbB2, ErbB3, and ErbB4 (Ref.2). ErbB2 also called Her2 (Heregulin-2) and ErbB3 are closely related to the EGFR/ErbB1, but unlike EGFR, ErbB2 is a ligandless receptor, whereas ErbB3 lacks tyrosine kinase activity. Hence, both ErbB2 and ErbB3 are active only in the context of ErbB heterodimers, and ErbB2-ErbB3 heterodimers, which are driven by Nrg (Neuregulin) ligands, are the most prevalent and potent complexes in terms of cell growth and transformation. The basis for the potency of signaling by the ligand-activated ErbB2-ErbB3 heterodimer lies in the fact that this dimer has the capacity to signal very potently, both through the Ras-ERK (Extracellular Signal Regulated Kinase) pathway for proliferation, and through the PI3K-Akt/PKB (Phosphatidylinositol-3 Kinase-Akt/Protein Kinase-B) pathway for survival. In addition, this receptor dimer evades downregulation mechanisms, leading to prolonged signaling.

Ligand-induced formation of the ErbB2-ErbB3 heterodimer at the cell surface leads to activation of several major pathways of signal transduction. This process results in enhanced cell survival and mitogenicity, and its deregulation can lead to tumorigenesis. Stimulation of ERK occurs upon ligand-induced activation of a receptor dimer, which binds GRB2 (Growth Factor Receptor-Bound Protein-2)through a phosphorylated tyrosine-based consensus site, or indirectly, through interaction with SHC. GRB2 is associated with SOS (Son of Sevenless), a guanine nucleotide exchange factor specific for Ras, and SOS activates Ras by exchanging GDP for GTP. In the GTPase active state, Ras interacts with Raf and stimulates a linear kinase cascade culminating in activation of ERK/MAPK (Mitogen-Activated Protein Kinases). ERK phosphorylates a variety of cytoplasmic and membranal substrates, and is rapidly translocated to the nucleus, where it activates a number of transcription factors including Sp1, PEA3, E2F, Elk1, Jun, Fos and Myc>c-Myc oncoprotein, which is a major transcription factor and regulator of cell cycle progression.

Another pathway is the P13K-Akt pathway. Activation of PI3K occurs through binding of the regulatory p85 subunit of the lipid kinase to a Phosphotyrosine consensus site on the receptor, leading to allosteric activation of the p110 catalytic subunit. p110 activation produces PIP3 (Phosphatidylinositol-3,4,5-Trisphosphate) from PIP2 (Phosphatidylinositol 4,5-Bisphosphate). The PH domain-containing proteins PDK1 (Phosphoinositide-Dependent Protein Kinase-1) and Akt/PKB are key mediators of PI3K signaling, and both are essential for the transforming effects of PI3K. Upon production of PIP2 and PIP3 following activation of PI3K by the ErbB2-ErbB3 receptor dimer, Akt is recruited to the plasma membrane by its PH domain, and is phosphorylated by PDK1. Akt phosphorylation causes its activation and translocation to the nucleus, where it acts upon its targets, which are either regulators of apoptosis or of cell growth, through inhibition of the proapoptotic proteins BAD (BCL2 Antagonist of Cell Death), GSK3 (Glycogen Synthase Kinase-3), and the transcription factor FKHR-L1. The tumor suppressor PTEN (Phosphatase and Tensin Homolog Deleted On Chromosome 10) is a lipid phosphatase, which dephosphorylates the 3’-OH position of PIP2 and PIP3, thereby reverting the activity of PI3K, and downregulating the activity of PDK1 and Akt. In addition, the PLC-Gamma (Phospholipase-C-Gamma) and the JAK/STAT (Janus Kinase/ Signal Transducers and Activators of Transcription Factor) pathways are indicated, with their resulting enhancement of transcription leading to cell proliferation. Activation of PLC-Gamma occurs through its SH2-mediated recruitment to phosphorylation- dependent docking sites on ErbB2, as well as recruitment through its PH domain to the plasma membrane. In its phosphorylated active form, PLC-Gamma hydrolyzes PIP2 into IP3 (Inositol Triphosphate), and DAG (Diacylglycerol). IP3 activates the release of Ca+2 (Calcium) from intracellular stores, and thereby activates Ca+2/Calm (Calmodulin) dependent kinases, as well as additional pathways, and it collaborates with DAG to stimulate PKC (Protein Kinase-C).

A major player acting downstream of ErbB2-ErbB3 is Cyclin-D1. A number of pathways lead from the receptors to enhanced activation of Cyclin-D1, thereby promoting cell cycle progression. The outcome of activation of these different signaling pathways depends on the cellular context, and can vary from proliferation to differentiation, migration, and even induction of apoptosis (Ref.3).