A cross-talk between TrkB and Ret tyrosine kinases receptors mediates neuroblastoma cells differentiation.
Understanding the interplay between intracellular signals initiated by multiple receptor tyrosine kinases (RTKs) to give the final cell phenotype is a major pharmacological challenge. Retinoic acid (RA)-treatment of neuroblastoma (NB) cells implicates activation of Ret and TrkB RTKs as critical step to induce cell differentiation. By studying the signaling interplay between TrkB and Ret as paradigmatic example, here we demonstrate 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 a key mechanism, since blocking either TrkB or Ret by small interfering RNA causes a failure in NB biochemical and morphological differentiation. Our results provide the first evidence that a functional transactivation between distinct tyrosine kinases receptors is required for an important physiological process.
Esposito
Carla Lucia
CL
Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
D'Alessio
Amelia
A
de Franciscis
Vittorio
V
Cerchia
Laura
L
D002454:Cell Differentiation; D002460:Cell Line; D006801:Humans; D009447:Neuroblastoma / Q000473:pathology*; D010766:Phosphorylation; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism*
D034741:RNA, Small Interfering; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D020813:Receptor, trkB