a cross-talk between trkb and ret tyrosine kinases receptors mediates neuroblastoma cells differentiation相声trkb与ret酪氨酸激酶受体介导神经母细胞瘤细胞分化.pdfVIP

A Cross-Talk between TrkB and Ret Tyrosine Kinases Receptors Mediates Neuroblastoma Cells Differentiation 1,3 2 1 1 Carla Lucia Esposito , Amelia D’Alessio , Vittorio de Franciscis , Laura Cerchia * 1 Istituto per l’Endocrinologia e l’Oncologia Sperimentale G. Salvatore, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy, 2 Cell Biology and Preclinical Models Unit, ` INT-Fondazione Pascale, Naples, Italy, 3 Dipartimento di Biologia e Patologia Cellulare e Molecolare ‘‘L. Califano’’, Universita di Napoli ‘‘Federico II’’, Naples, Italy Abstract 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. Citation: Esposito CL, D’Alessio A, de Franciscis V, C