EGFR family

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Structure of the EGFR family receptor

Identifiers
Symbol	?
Pfam	PF00000
Pfam clan
InterPro	IPR000000
SMART
PROSITE
CATH
MEROPS
SCOP2

The EGFR family, also known as the ErbB family, is a group of four closely related receptor tyrosine kinases that are essential for various cellular processes, including cell growth, survival, proliferation, and differentiation. The family consists of four members: EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). These receptors are activated by binding to specific ligands, leading to the activation of downstream signaling pathways.

Structure

Each member of the EGFR family is a transmembrane protein with an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular tyrosine kinase domain. The extracellular domain is responsible for ligand binding, while the intracellular domain transduces the signal by phosphorylating tyrosine residues on the receptor itself and on downstream signaling proteins.

Function

The EGFR family plays a critical role in the regulation of cell growth and differentiation. Upon ligand binding, these receptors undergo dimerization, which is a prerequisite for their activation. Dimerization can occur between identical receptors (homodimerization) or between different family members (heterodimerization). This dimerization leads to the activation of the intrinsic kinase activity, resulting in autophosphorylation of specific tyrosine residues in the cytoplasmic domain.

The phosphorylated tyrosines serve as docking sites for various signaling molecules, initiating a cascade of downstream signaling pathways, including the Ras/MAPK pathway, the PI3K/AKT pathway, and the JAK/STAT pathway. These pathways regulate diverse cellular outcomes, such as proliferation, survival, migration, and differentiation.

Clinical Significance

Dysregulation of EGFR family signaling is implicated in the development and progression of various cancers. Overexpression, mutation, or amplification of EGFR family members can lead to uncontrolled cell proliferation and survival, contributing to oncogenesis. For example, mutations in the EGFR gene are commonly found in non-small cell lung cancer, while HER2 overexpression is associated with breast cancer.

Targeted therapies have been developed to inhibit EGFR family signaling in cancer. These include monoclonal antibodies, such as trastuzumab for HER2-positive breast cancer, and small molecule tyrosine kinase inhibitors, such as erlotinib and gefitinib for EGFR-mutant lung cancer.

Research Directions

Current research is focused on understanding the mechanisms of resistance to EGFR-targeted therapies and developing new strategies to overcome this resistance. Additionally, the role of EGFR family members in other diseases, such as cardiovascular and neurological disorders, is an area of active investigation.

Also see

• Receptor tyrosine kinase
• Signal transduction
• Cancer biology
• Monoclonal antibody therapy