On Trk--the TrkB signal transduction pathway is an increasingly important target in cancer biology

Abstract

In the beginning, Trk was an oncogene. Yet Neurotrophin-Trk signaling came to preeminence in the field of neurobiology. Now it is appreciated that Trks regulate important processes in nonneuronal cells and, in addition to their impact on tumors of neural origin, may contribute to the pathogenesis of carcinomas, myelomas, and prostate and lymphoid tumors. Although mutations and rearrangements of Trk are seen only sporadically in human cancers, such as medullary thyroid carcinoma, a number of recent studies indicate that expression of TrkB contributes to tumor pathology. In neuroblastoma, TrkA expression marks good prognosis which TrkB and Brain-derived neurotrophic factor (BDNF) expression marks poor prognosis. Activation of the BDNF/TrkB signal transduction pathway also stimulates tumor cell survival and angiogenesis and contributes to resistance to cytotoxic drugs and anoikis, enabling cells to acquire many of the characteristic features required for tumorigenesis. Small molecule inhibitors, such as Cephalon's CEP-701, are in phase 1 and 2 clinical trials, and a series of AstraZeneca Trk inhibitors are poised to enter the clinic. As monotherapy, inhibitors may be effective only in tumors with activating Trk mutations. Important clinical follow-up will be the assessment of Trk inhibitors in combination with standard chemo- or radiotherapy or other signal transduction pathway inhibitors.

Figure 1

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 cytoplamic proteins such as Shc, 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 and 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.