A cross-talk between TrkB and ret tyrosine kinase receptors mediates neuroblastoma cells differentiation

Abstract

Understanding the interplay between intracellular signals initiated by multiple receptor tyrosine kinases (RTKs) to give the final cell phenotype is a major pharmacological challege, Retinoic acid (RA)-treatment of neuroblastoma (NB) cells implicates activation of Ret and TrkB RTKs as critical step ti induce cell differentiation. By studying the signaling interplay between TrkB and Ret as paradigmatic example, here we demostrate the existence of a cross talk mechanism between the two unrelated receptors that is needed to induce the cell differentiation. Indeed, we show that TrkB receptor promotes Ret phosphorylation by a mechanism that does not require GDNF. This reveals to be key mechanism, since blocking either TrkB or Ret by small interfering RNA causes a failure in NB biochemical and morphological diffentiation. Our results provide the first evidence that a functional transactivation between distinct tyrosine kinase receptors is required for an important physiological process. © 2008 Esposito et al.