Boster Pathways-> Cytokines

ErbB2-ErbB3 Heterodimers Pathway

Members of the ErbB family and several of their ligands are frequently overexpressed, amplified, or mutated in a variety of types of cancer, making them attractive therapeutic targets.

Overview of ErbB2-ErbB3 Heterodimers Pathway

ErbB (erythroblastic oncogene B) is a member of the epidermal growth factor receptor family. It is composed of three domains: an extracellular domain, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. The ErbB family in humans consists of four members: ErbB1 (Her1), ErbB2 (Her2), ErbB3 (Her3), and ErbB4 (Her4) (Her4).

ErbB1 is also known as EGFR (epidermal growth factor receptor). EGFR is normally expressed on the epithelial cell surface. However, it is frequently overexpressed in certain tumor cells. Overexpression of EGFR is associated with tumor cell metastasis, invasion, and poor prognosis.

By binding to EGF or TGF- (transforming growth factor ), the EGFR is activated. The inactive monomer of activated EGFR is converted to an active homodimer.

ErbB2-ErbB3 Heterodimers Pathway

The formation of the ErbB2-ErbB3 heterodimer at the cell surface is induced by ligands and results in the activation of several major signal transduction pathways. This process promotes cell survival and proliferation, and its dysregulation can result in tumorigenesis. Stimulation of ERK occurs when a ligand activates a receptor dimer, which either directly or indirectly binds GRB2 (Growth Factor Receptor-Bound Protein-2) via a phosphorylated tyrosine-based consensus site. GRB2 interacts with SOS (Son of Sevenless), a Ras-specific guanine nucleotide exchange factor that activates Ras by exchanging GDP for GTP. Ras interacts with Raf in the GTPase active state and initiates a linear kinase cascade that results in the activation of ERK/MAPK (Mitogen-Activated Protein Kinases). ERK phosphorylates a variety of cytoplasmic and membranous substrates and is rapidly translocated to the nucleus, where it activates a number of transcription factors, including Sp1, PEA3, E2F, Elk1, Jun, and Fos, as well as the Myc>c-Myc oncoprotein, a major transcription factor and regulator of cell cycle progression.

The P13K-Akt pathway is another possible pathway. PI3K is activated when the regulatory p85 subunit of the lipid kinase binds to a Phosphotyrosine consensus site on the receptor, allosterically activating the catalytic p110 subunit. PIP3 (Phosphatidylinositol-3,4,5-Trisphosphate) is formed when p110 is activated (Phosphatidylinositol 4,5-Bisphosphate). PDK1 (Phosphoinositide-Dependent Protein Kinase-1) and Akt/PKB are critical mediators of PI3K signaling, and both are required for PI3transformative K's effects. Akt is recruited to the plasma membrane by its PH domain and phosphorylated by PDK1 in response to the production of PIP2 and PIP3 following PI3K activation by the ErbB2-ErbB3 receptor dimer. Akt phosphorylation results in its activation and translocation to the nucleus, where it inhibits the proapoptotic proteins BAD (BCL2 Antagonist of Cell Death), GSK3 (Glycogen Synthase Kinase-3), and the transcription factor FKHR-L1. PTEN (Phosphatase and Tensin Homolog Deleted On Chromosome 10) is a lipid phosphatase that dephosphorylates the 3'-OH position of PIP2 and PIP3, reverting PI3K activity and downregulating PDK1 and Akt activity. Additionally, the PLC-Gamma (Phospholipase-C-Gamma) and JAK/STAT (Janus Kinase/Signal Transducers and Activators of Transcription Factor) pathways are highlighted, with their associated transcriptional enhancement leading to cell proliferation. PLC-Gamma is activated via its SH2-mediated recruitment to phosphorylation-dependent docking sites on ErbB2 and via its PH domain recruitment to the plasma membrane.

PLC-Gamma hydrolyzes PIP2 into IP3 (Inositol Triphosphate) and DAG in its phosphorylated active form (Diacylglycerol). IP3 stimulates the release of Ca+2 (Calcium) from intracellular stores, thereby activating Ca+2/Calm (Calmodulin) dependent kinases and additional pathways, and it works in conjunction with DAG to stimulate PKC (Protein Kinase-C).

Cyclin-D1 is a significant player acting downstream of ErbB2-ErbB3. Numerous pathways connect the receptors to increased Cyclin-D1 activation, thereby promoting cell cycle progression. The outcome of activating these various signaling pathways is context-dependent and can range from proliferation to differentiation, migration, and even apoptosis induction.