γ-Secretase Cleavage and Nuclear Localization of ErbB-4 Receptor Tyrosine Kinase

Abstract

ErbB-4 is a transmembrane receptor tyrosine kinase that regulates cell proliferation and differentiation. After binding of its ligand heregulin (HRG) or activation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA), the ErbB-4 ectodomain is cleaved by a metalloprotease. We now report a subsequent cleavage by gamma-secretase that releases the ErbB-4 intracellular domain from the membrane and facilitates its translocation to the nucleus. gamma-Secretase cleavage was prevented by chemical inhibitors or a dominant negative presenilin. Inhibition of gamma-secretase also prevented growth inhibition by HRG. gamma-Secretase cleavage of ErbB-4 may represent another mechanism for receptor tyrosine kinase-mediated signaling.

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

“…As a component of γ-secretase complex, nicastrin is also involved in the recognition and cleavage of a variety of other integral membrane proteins such as Notch, Nectin-1a, E-cadherin and ErbB-4 receptor [26,32,35,50]. There is evidence that peptides generated from these cleavage are capable of modulating functions in the developing as well as the adult brain [10].…”

Identification of novel nuclear localization signal within the ErbB-2 protein

“…The NLS reported in this study is underlined. In the case of ErbB4, the intracellular domain was reported to be present in the nucleus [14,15]. It was recently reported that full-length ErbB2, like EGFR and ErbB3, translocates to the nucleus [12].…”

“…The reported tyrosine kinase receptors include four members of ErbB family [11][12][13][14][15] and other tyrosine kinase receptors like VEGF receptor [16], FGF receptor [17,18] and NGF receptor [19]. However, the four members of ErbB family were translocated in the nucleus in different form.…”

“…In the case of EGFR, the complete ligand-full length receptor complex was reported to be present in the nucleus [11]. Nuclear ErbB3 was localized to the nucleus as full-length protein [13], while only the intracellular domain ErbB4 can be targeted to the nucleus [14,15]. In the case of ErbB2, it has been recently demonstrated that full-length ErbB2 is located to the nucleus by a combination of electron microscopy, fluorescence microscopy, immunohistochemistry and biochemical fraction [12].…”

Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms

“…Cleavage by TACE triggers a second cleavage of ErbB4 involving g-secretase activity (Lee et al, 2002). As a result the intracellular domain (ICD) is released from the cell membrane and translocates to the nucleus where it may function as a transcriptional regulator (Ni et al, 2001;Komuro et al, 2003;Ma¨a¨tta¨et al, 2006;Schlessinger and Lemmon, 2006). Consistent with the hypothesis that ErbB4 isoforms differ in their function in tumorigenesis, the cleavable ErbB4 JM-a CYT-2 isoform, but not its noncleavable counterpart JM-b CYT-2, demonstrates ligand-independent activity and promotes cancer cell growth (Ma¨a¨tta¨et al, 2006).…”