Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Julhash U. Kazi
  • Nuzhat N. Kabir
  • Lars Rönnstrand
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101775


 Bex;  DXS6984E;  HGR74;  NADE;  NGFRAP1

Historical Background

The Brain-Expressed X-linked (BEX) is a family of five proteins including BEX1, BEX2, BEX3, BEX4, and BEX5 (Kazi et al. 2015). BEX-family proteins are characterized by a highly conserved BEX domain (Fig. 1). Function of the BEX domain is still poorly understood. Recent studies identified a role of BEX domain containing proteins in growth control. All BEX genes cluster to the human Xq22 chromosome. BEX3 was the first BEX-family protein described and was initially named HGR74 (Rapp et al. 1990).
BEX3, Fig. 1

BEX family proteins. All BEX family proteins share a characteristic BEX domain. BEX2 and BEX3 have an uncharacterized N-terminal region

BEX3 Gene and Spice Variants

Human BEX gene encodes three splice variants known as BEX3 isoforms a, b and c (Fig 2). Although all three isoforms contain an intact BEX domain, isoform c has an N-terminal uncharacterized region with proline-rich (PXXP) motif, indicating that isoform c might associate with SRC-homology 3 (SH3) domain-containing proteins. BEX3 expression was described in various human tissues including testis, prostate, ovarian granulosa cells, and seminal vesicles (Rapp et al. 1990). The mouse homolog of BEX3 is known as Nerve Growth Factor Receptor Associated Protein 1 (NGFRAP1). Mouse BEX3 was identified as a nerve growth factor receptor (p75NTR)-associating protein and was named NADE (Mukai et al. 2000). In mouse, BEX3 expression has been described in brain, heart, lung, stomach, small intestine, and muscle tissues (Mukai et al. 2000). BEX3 expression was also described in pillar cells (Sano et al. 2001), and higher expression was detected during mouse embryonic development (Sharov et al. 2003). Mouse BEX3 has a short sequence of nuclear export signal (NES). Therefore, BEX3 is localized both to the cytosol and also to the nucleus (Mukai et al. 2000; Alvarez et al. 2005).
BEX3, Fig. 2

BEX3 splice variants. BEX3 gene encodes three different splice variants. All three isoforms have a functional BEX domain. Isoform c is the longest BEX3 isoform having a N-terminal region with proline-rich (PXXP) sequence

BEX3 in Neurotrophin Receptor Signaling

The nerve growth factor (NGF) and its receptor (p75NTR) have been well studied for their involvement in development and maintenance of the nervous system (Descamps et al. 2001). BEX3 interacts with the transmembrane receptor p75NTR in response to NGF in PC12 cells (Mukai et al. 2000) and in cortical neurons (Park et al. 2000). NGF-induction elevates BEX3 expression in oligodendrocytes (Mukai et al. 2000). The association of BEX3 with p75NTR is mediated through the death domain of p75NTR and is required for NGF-induced apoptosis (Mukai et al. 2000; Mukai et al. 2002). Furthermore, BEX3 associates with the adaptor protein 14-3-3ε (YWHAE). The 14-3-3 family proteins associate with phospho-serine and phospho-threonine containing proteins, regulating a wide range of cellular processes including apoptosis, development, proliferation, and signal transduction (Zhao et al. 2011). BEX3 and 14-3-3ε complex formation is necessary for NGF-induced p75NTR/BEX3-mediated apoptosis in oligodendrocytes and PC12nnr5 (Kimura et al. 2001). The tuberous sclerosis complex 1 (TSC1) gene product Hamartin forms complex with BEX3, and siRNA-mediated knockdown of TSC1 gene in PC12h cells was shown to protect cells from NGF-induced apoptosis indicating that BEX3-Hamartin association is also required for NGF-induced apoptosis in PC12 cells (Yasui et al. 2007). Therefore, it is likely that BEX3 forms a multi-protein complex to induce apoptosis in PC12 cells in response to NGF. Another NGF receptor, the tropomyosin-related kinase A (TRKA) constitutively binds to BEX3 and both TRKA and BEX3 are expressed in embryonic rat dorsal root ganglia (DRG) neurons, further suggesting a role of BEX3 in neuronal development (Calvo et al. 2015). BEX3 has two boxes which contain sequences that are targets for ubiquitination. Expression of BEX3 was detected in PCNA and PC12 cells after inhibition of proteasome activity suggesting that BEX3 is a target of ubiquitination-dependent degradation (Mukai et al. 2000; Mukai et al. 2003). Furthermore, BEX3 was found to be rapidly degraded in the proteasomes (Mukai et al. 2000; Alvarez et al. 2005). Collectively, the current data suggest that BEX3 forms multi-protein complexes to induce apoptosis (Fig. 3).
BEX3, Fig. 3

BEX3 in NGF receptor signaling. Upon NGF-stimulation BEX3 binds with NGF-receptor p75NTR and form complex with 14-3-3ε and Harmartin inducing apoptosis

Role of BEX3 in Cancer

BEX proteins play differential roles in cancer. BEX1 has been shown to be a tumor suppressor while BEX2 acts as an oncogene (Kazi et al. 2015; Lindblad et al. 2015). There are a few studies describing the involvement of BEX3 in cancer. The human ovarian carcinoma cell line (PA-1) and the mouse teratocarcinoma cell line (F9) express BEX3 (Kim et al. 2004). In PA-1 and F9 cell lines, BEX3 was found to be associated with mitochondria suggesting a role in regulation of mitochondrial function. Breast cancer cell lines express the NGF receptors p75NTR and TRKA, as well as BEX3 (Descamps et al. 2001; Tong et al. 2003) indicating a possible involvement of BEX3 in breast cancer. Overexpression of BEX3 in MDA-MB-231 human breast cancer cells suppressed in vivo tumor formation suggesting that BEX3 acts as tumor suppressor in breast cancer (Tong et al. 2003). Furthermore, BEX3 associates with SMAC (Yoon et al. 2004). SMAC is a mitochondrial protein that induces cytochrome c-dependent caspase activation (Du et al. 2000). Association of BEX3 with SMAC inhibits XIAP-mediated SMAC ubiquitination but promotes TRAIL-induced apoptosis in MCF7 breast cancer cells (Yoon et al. 2004). Thus, in breast cancer BEX3 appears to be a proapoptotic gene.


Role of BEX proteins in human pathophysiology has not been extensively studied. Current studies suggest that BEX3 plays an important role in signaling by the nerve growth factor receptors. BEX3 induces apoptosis by forming multi-protein complexes in response to NGF stimulation, which is required apoptosis. Therefore, BEX3 expression is required for maintaining basal levels of NGF signaling. Involvement of BEX3 in cancer is also evident. BEX3 acts as a tumor suppressor in breast cancer by inducing apoptosis.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Julhash U. Kazi
    • 1
    • 2
  • Nuzhat N. Kabir
    • 2
  • Lars Rönnstrand
    • 1
  1. 1.Division of Translational Cancer Research, Department of Laboratory MedicineLund UniversityLundSweden
  2. 2.Laboratory of Computational BiochemistryKN Biomedical Research InstituteBarisalBangladesh