HER4, also known as ErbB4, is a protein that acts as a receptor on the surface of cells. It belongs to a larger family of receptors involved in transmitting signals into the cell. This signaling plays a part in a variety of cellular processes, influencing how cells grow, divide, and specialize.
The HER Family Context
HER4 is one of four related receptor tyrosine kinases that make up the epidermal growth factor receptor (EGFR) or HER family, which also includes HER1 (EGFR), HER2, and HER3. These proteins are generally involved in regulating cell growth and survival pathways. Each HER protein has an extracellular domain for ligand binding, a single transmembrane domain, and a cytoplasmic domain containing an active tyrosine kinase.
What sets HER4 apart is its unique signaling properties and diverse roles, including instances where it can inhibit cell growth. While all HER receptors can form homodimers or heterodimers upon ligand binding, HER4 has specific ligands like neuregulins (NRG1, NRG2, NRG3, NRG4) and some epidermal growth factor (EGF) family members. This distinct ligand binding profile contributes to its varied biological outcomes compared to other HER family members.
HER4’s Diverse Biological Roles
HER4 is present in many human tissues during development and adulthood. It plays a role in the formation and functioning of the cardiovascular system, including the heart. For instance, HER4 is necessary for cardiac muscle differentiation during embryonic development and for cardiomyocyte proliferation after birth.
The protein also contributes to the development and function of the nervous system, involved in processes such as neural crest cell migration and axon guidance in the embryonic central nervous system. HER4 also plays a role in the development and differentiation of mammary glands, influencing both growth and differentiation of mammary epithelial cells. Its activity is lower during rapid cell proliferation, such as puberty and early pregnancy, and higher during phases of differentiation, like late pregnancy and early lactation.
HER4’s functions are complex, sometimes promoting cell growth and differentiation, and at other times inhibiting it or inducing cell death. This dual capacity stems from its unique proteolytic cleavage, which releases a soluble intracellular domain (s80HER4). This domain can move into the nucleus to influence gene expression, contributing to balanced tissue maintenance.
HER4 in Disease Development
HER4’s involvement in disease depends on the specific context, with its role often varying even within the same disease type. In cancer, for example, HER4 can sometimes suppress tumor growth, particularly in certain breast cancers. Studies suggest HER4 activity can induce programmed cell death (apoptosis) in breast cancer cells.
Conversely, in other cancer types, HER4 can promote tumor progression. Overexpression of HER4 has been linked to the development of some cancers, such as gastric cancers where increased levels promote cell proliferation. Similarly, high HER4 expression in osteosarcoma cells promotes proliferation and metastasis.
HER4’s dysregulation also extends beyond cancer, potentially contributing to other health conditions. In neurological disorders, for instance, HER4 signaling is implicated in conditions like neuroblastoma, a common childhood cancer. Overexpression of HER4 in neuroblastoma cells can lead to increased chemoresistance, suggesting a role in treatment failure. Additionally, HER4’s functions in the cardiovascular system suggest its dysregulation could contribute to cardiac diseases, though specific pathologies are still under investigation.
Targeting HER4 in Therapeutics
Given its diverse roles, researchers are investigating ways to modulate HER4 activity for therapeutic purposes. HER4’s complex nature, acting as both a growth promoter and inhibitor depending on cellular context, presents a challenge for drug development. Despite this, its involvement in various diseases, especially cancer, makes it a target of interest.
Strategies include developing HER4 antagonists, compounds that inhibit the receptor’s activity. By blocking HER4 signaling, these antagonists aim to control cellular processes contributing to disease, such as uncontrolled cell proliferation in cancer. Current research primarily focuses on oncology, exploring HER4 as a target in breast, ovarian, and colorectal cancers where it may promote tumor growth.
Beyond cancer, the therapeutic potential of HER4 modulation is also being explored in other fields. This includes neurological conditions, where HER4’s role in neurodevelopment and neuronal function could be leveraged. Its involvement in cardiovascular system development also suggests potential applications in treating heart-related conditions. These ongoing research efforts aim to uncover new treatment options by specifically targeting HER4’s signaling pathways.