On Trk—The TrkB Signal Transduction Pathway Is an Increasingly Important Target in Cancer Biology

Schematic representation of Trk receptor tyrosine kinases and major signal transduction pathways. The trk receptors have an extracellular ligand-binding domain, a singular transmembrane region, and an intracellular region of variable length. The round green filled circles represent the cysteine-rich regions, which are separated by fibronectin type III repeats (jagged line). The open green circles represent the Ig-like domains that bind the dimeric BDNF monomers leading to dimerization of the TrkB receptors and activation of the intracellular TrkB-tyrosine kinase (TK) domain (rectangle filled with circles). Activation of the TrkB-TK leads to phosphorylation (P) of a number of tyrosines (Y) in the TK domain, as well as the juxtamembrane domain. These PY residues serve as docking sites for cytoplasmic proteins, such as Shc and PLCγ, whose recruitment in turn leads to activation of downstream mediators of the MAPK, PLCγ and PI-3 kinase pathways. Ultimately, these signals are transduced to the nucleus to mediate transcriptional programs that regulate cellular functions, such as synaptic plasticity, differentiation, growth, survival, and motility. Other members of the Trk family, TrkA and TrkC, are depicted to illustrate the structural conservation of this gene family. P75 is a pan-neurotrophin (NT) receptor, which is structurally in the Death Receptor family of membrane-bound receptors.