A network map of BDNF/TRKB and BDNF/p75NTR signaling system

Abstract

Neurotrophic factors are growth factors, which play an essential role in the development and maintenance of nervous system. These include members of the nerve growth factor (NGF) family, known as neurotrophins. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), neurotrophin 4 (NT4/5) and neurotrophin 6 (NT-6) constitute the family of neurotrophins (Barbacid 1995). The identification of neurotrophic factors began from the search for target-derived molecules, which act on neurons and promote their survival (Lindsay 1996). BDNF is one such essential survival factor. BDNF was first isolated and purified from pig brain (Barde et al. 1982). BDNF, encoded by the BDNF gene, is the second member of the neurotrophin family after NGF (Timmusk et al. 1993). BDNF, like other neurotrophins, exists as a homodimer. It is synthesized as a precursor molecule, proBDNF (32 kDa), which is cleaved to form the mature and biologically active form of BDNF (∼13 kDa) (Negro et al. 1994). It is expressed throughout the central nervous system (Leibrock et al. 1989) and also in peripheral tissues including muscle, liver, pancreas, colon, duodenum, lung, kidney and bladder (Lommatzsch et al. 1999). The dimerized BDNF binds to the tyrosine kinase receptor, tropomyosin-related kinase B (TrkB), leading to activation of various signaling modules. Trk was first identified as an oncoprotein in human tumors (Martin-Zanca et al. 1986). The Trk family of receptors includes TrkA, which binds to NGF (Kaplan et al. 1991); TrkB, which is the receptor for BDNF and NT-4 (Klein et al. 1989); and TrkC, the receptor for NT-3 (Lamballe et al. 1991). TrkB is an 821 amino acid long glycoprotein, encoded by the NTRK2 gene. It comprises of a signal peptide followed by an extracellular domain, a transmembrane domain and a cytoplasmic region consisting of the tyrosine kinase domain (Nakagawara et al. 1995). TrkB is expressed in the central and peripheral nervous system (Allen et al. 1994). Like other neurotrophins, BDNF also binds to nerve growth factor receptor (NGFR), also known as p75 neurotrophin receptor (p75NTR), albeit with a low-affinity (Chao et al. 1986). Binding of BDNF to TrkB results in the dimerization of the receptor and activation of its cytoplasmic kinase domain (Ohira et al. 2001; Wu et al. 1996), which results in the recruitment of adaptor proteins to the receptor, which in turn leads to the activation of intracellular signaling cascades including RAS/ERK pathway, PI3K/AKT pathway, PLC/PKC pathway and NFκB pathway. BDNF/TrkB signaling is essential for growth, differentiation and survival of neurons. It is also important for neuronal morphogenesis and synaptic plasticity (Binder and Scharfman 2004). BDNF also plays a major role in other processes such as energy metabolism (Matthews et al. 2009), behavior, learning, memory (Hall et al. 2000), pain (Pezet et al. 2002) and apoptosis (Yeiser et al. 2004). BDNF is implicated in Alzheimer’s disease (Ferrer et al. 1999), Huntington’s disease (Zuccato et al. 2001), epilepsy (Takahashi et al. 1999) and bipolar disorder (Neves-Pereira et al. 2002). However, despite its biological significance, molecular events induced by either BDNF/TrkB or BDNF/p75NTR interactions, were not organized into a signaling network. As a part of the ongoing NetPath project, which aims at the development of a centralized resource for human signaling pathways (Kandasamy et al. 2010; Raju et al. 2011b), we have documented molecular reactions induced by several signaling systems by systematically reviewing published reports and assembled them in the form of signaling pathways. We have previously published molecular networks of signaling induced by prolactin (Radhakrishnan et al. 2012), oncostatin M (Dey et al. 2012); corticotropin releasing hormone (Subbannayya et al. 2013) and advanced glycation end-products (Soman et al. 2013). Similarly, as BDNF signaling pathway is of immense biomedical interest, we analyzed literature pertaining to BDNF-induced signaling events and developed a graphical network map of BDNF/TrkB and BDNF/p75NTR signaling pathways.