HER4 Intracellular Domain (4ICD) Activity in the Developing Mammary Gland and Breast Cancer

Abstract

The HER4 receptor tyrosine kinase was the final member of the EGFR-family to be discovered. In contrast to the other three members of this receptor family which function primarily as mitogenic effectors in the breast, HER4 appears to have multiple divergent functions in the normal and malignant breast. Interestingly, the majority of HER4 activities in the breast including pregnancy induced differentiation and lactation initiation, transcriptional activation, tumor cell proliferation, growth suppression, and induction of apoptosis appear to be mediated by an independently signaling soluble HER4 intracellular domain (4ICD). The 4ICD can accumulate within the nucleus or mitochondria and subcellular localization of 4ICD in part determines the physiological response of breast cells to 4ICD action. Here I will discuss the evidence supporting the role of 4ICD as the critical effector of HER4 signaling in the breast. In addition a developmental and temporal model of 4ICD action in the normal breast and during the progression of breast cancer will be presented to explain the paradox of divergent HER4 and 4ICD activities. KeywordsEGFR-family; Estrogen receptor; BCL-2 family; Apoptosis; Transcription Proteolytic Processing of HER4 to Generate a Soluble HER4 Intracellular Domain (4ICD)It is well accepted that the HER4 transmembrane receptor undergoes regulated intramembrane proteolysis (RIP) at the cell surface to release a soluble intracellular domain (ICD); a property that remains unique among EGFR-family members. An excellent review of the molecular details underlying HER4 RIP was recently published elsewhere [1]. In summary, ectodomain cleavage of the 180 kDa HER4 cell surface receptor is mediated by tumor necrosis factor α converting enzyme (TACE), a member of the ADAM metalloproteinase family referred to as ADAM17 [2]. Following TACE cleavage the ca. 120 kDa HER4 ectodomain, which includes the ligand binding region, is shed into the extracellular milieu while the remaining 80 kDa cleavage product (m80) is retained as a transmembrane peptide. The m80 harbors an active tyrosine kinase [3] and a carboxyl terminus with several potential tyrosine phosphorylation sites. Although the m80 is phosphorylated it remains unclear if this membrane tethered peptide transmits cellular signals. The HER4 m80 however is a substrate for presenilin-dependentsecretase cleavage. This RIP event results in membrane release of a soluble 4ICD. Depending upon specific cellular properties, that we are beginning to understand, membrane released 4ICD may translocate to the nucleus or remain in the cytosol where mitochondrial accumulation has e-mail: fjones@tulane.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript been observed (Fig. 1). The 4ICD is emerging as a unique independently signaling molecule and the impact of 4ICD signaling in the breast will be discussed in detail here. [16][17][18]. Although there is increasing evidence to suggest that phosphorylation of γ-secretase and its substra...

Receptor Tyrosine Kinases in the Nucleus

“…It is clear that ErbB-4 is functionally involved in mammary development in the animal (Jones 2008). ErbB-4 nuclear localization has been observed in normal and tumor mammary tissue and exogenous ICD expression provokes differentiation events (Muraoka-Cook et al 2006).…”

Expression of the Epidermal Growth Factor Receptors and Ligands in Paired Samples of Normal Breast Tissue, Primary Breast Carcinomas and Lymph Node Metastases

“…The functional significance of this is controversial [39]. The HER4 receptor appears to possess divergent functions demonstrated in vitro to depend on the isoform of the receptor [40] [41]. The HER4 response can also depend on the activating ligand [42], or the localization in the cell compartments (membrane bound, cytoplasmatic or in the nucleus) [43].…”

Analysis of regulatory mechanism after ErbB4 gene mutation based on local modeling methodology

“…The BH3-only protein acts as a 'sensor' of apoptosis stimulation and is regarded as a necessary effective factor for initiating apoptosis. Naresh et al (2006) found that HER4 intracellular domain (4ICD) of ErbB4 is a BH3-only protein that can promote the apoptosis of breast cancer cells; Jones (2008) found that the notch intracellular domain of ErbB4 activates the growth of mammary tissue and improves the occurrence of breast cancer and apoptosis of breast cancer cells. However, the specific action mechanism by which the ErbB4 intracellular region involved in regulation remains unclear.…”