Expression of neuregulin 4 splice variants in normal human tissues and prostate cancer and their effects on cell motility

Abstract

The neuregulin 4 gene encodes at least five different variants (designated A1, A2, B1, B2 and B3) produced as a result of alternative splicing. We have determined their sites of expression in normal human adult tissues using isoform-specific antibodies. Their expression is cell type specific and differs in subcellular location suggesting that they may have varied functions in these contexts. We have shown in a panel of prostate cancers that each form is present to differing degrees, and that principal component analysis indicates that there are three patterns of expression. Some isoforms were positively correlated with high prostate-specific antigen levels and others were inversely associated with Gleason score. Synthetic, refolded A forms promoted lamellipodia and filopodia formation in cells expressing the ErbB4 (CTa) receptor and stimulated cell motility in wound healing assays. The data suggest that the different forms have varied sites of expression and function, and this includes effects on cell architecture and motility.

Elevated circulating Neuregulin4 level in patients with diabetes

“…Wang et al focused only on the Nrg4 expression within the adipose tissue, and the transgenic regulation of Nrg4 expression was also adipose‐selective, while Nrg4 is not exclusively expressed in adipose tissues. Instead, pancreas, stomach, and muscle are all the repertoire of Nrg4 and could contribute to the circulatory Nrg4 level . The Nrg4 expression pattern of these tissues could be distinctly different from that in adipose tissue under the condition of metabolic disorders, thus making the overall Nrg4 expression throughout the whole body a totally different story.…”

Neurological dysfunctions associated with altered BACE1‐dependent Neuregulin‐1 signaling

“…Expression of Nrg4 appears to be more restricted, mainly to pancreas and muscle, and is required for epithelial cell survival (Hayes et al . ; Bernard et al . ; McElroy et al .…”

“…Only two Nrg4 isoforms have the transmembrane domain encoded by exon 6. Expression of Nrg4 appears to be more restricted, mainly to pancreas and muscle, and is required for epithelial cell survival (Hayes et al 2011;Bernard et al 2012;McElroy et al 2014). If not synthesized as secreted isoforms, Nrg2, Nrg3, and Nrg4 have a single pass type I membrane domain and all contain EGF-like domains (Fig.…”

Analysis of protein isoforms: Can we do it better?

“…Neuregulins (NRG 1–4) and their corresponding splice variants play important roles in mammary gland development, they are expressed at high levels in breast cancer and they are related to prostate cancer . For example, NRG 4 has at least five splice variants (A1, A2, B1, B2, and B3), their expressions are cell specific and they differ in subcellular location.…”

“…In prostate cancer, each variant has a different degree and pattern of expression and function e.g. the effects on cell architecture and motility .…”