ErbB2-ErbB3 Heterodimers
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ErbB2-ErbB3 Heterodimers

The ErbB tyrosine kinases (epidermal growth factor receptor (EGFR), ErbB2/HER2, ErbB3, and ErbB4) are cell surface growth factor receptors widely expressed in many developing mammalian tissues, including in the intestinal tract. Signaling elicited by these receptors promotes epithelial cell growth and survival, and ErbB ligands have been proposed as therapeutic agents for intestinal diseases of pediatric populations, including inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), and inflammation associated with total parenteral nutrition (TPN) (Ref.1).

ErbB3 receptors are unique members of the erbB receptor tyrosine kinases (RTKs), which are often aberrantly expressed and/or activated in human cancers. Unlike other members in the family, erbB3 lacks or has impaired kinase activity. To transduce cell signaling, ErbB3 has to interact with other RTKs and to be phosphorylated by its interactive partners, of those, ErbB2 is the most important one (Ref.2).On the other hand, ERBB2 is an orphan receptor that tyrosine phosphorylates its heterodimerization partners. Heterodimers of the ligand- binding-deficient ERBB2 (HER2) receptor and the kinase impaired ERBB3 (HER3) create a potent mitogenic signal, but the phosphorylation of ERBB2 in this context presents a challenge to established models of phosphorylation in trans. Majority of MAPK signaling emanates from ERBB2, whereas ERBB3 dominates signaling through the PI3K/AKT pathway. In addition, the ErbB receptors activate other pathways, such as STATs,PLCs and JNK. These molecules further regulate the activities of key transcriptional factors, such as Jun, Fos and Myc, leading to the modulation of various aspects of cell function including survival, proliferation, and migration.ErbB3 binds to neuregulins (NRGs), NRG1 and NRG2 (Ref.3).

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 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) (Ref.4 and 5). 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.6).

ErbB3 is frequently co-expressed with other RTKs in cancer cells to activate oncogenic signaling, such as phosphoinositide-3-kinase/protein kinase B (Akt) pathway, mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) pathway, Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway, etc. and thereby promote tumorigenesis. Activation of erbB3 signaling plays an important role in the progression of a variety of tumor types, such as erbB2-overexpressing breast cancer, castration- resistant prostate cancer, platinum refractory/resistant ovarian cancer, epidermal growth factor receptor TKI-resistant non-small-cell lung cancer, and others (Ref.2).