Sprouty family of proteins regulates organogenesis and carcinogenesis through the signaling caused by RET tyrosine kinase

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The Sprouty family of proteins includes important regulators of downstream signaling initiated by receptor tyrosine kinases. In the present study, we investigated the role of Sprouty proteins in intracellular signaling via RET tyrosine kinase. Expression of Sprouty family proteins in HEK293T cells transfected with RET and GFRα1 genes significantly reduced sustained activation of ERK, whereas their expression had no remarkable influence on the activation of p38, Akt and JNK. Since expression of Sprouty2 was efficiently induced by GDNF in TGW human neuroblastoma cells expressing RET and GFRα1, we further investigated the role of Sprouty2 in growth and differentiation of TGW cells. Expression of wild-type Sprouty2 (WT-SPRY2) decreased the growth of TGW cells. In contrast, expression of a dominant negative form of Sprouty2 (MT-SPRY2, with a mutated tyrosine residue) enhanced cell proliferation. In addition, expression of WT-SPRY2 reduced GDNF-dependent neurite outgrowth of TGW cells, where … More as expression of MT-SPRY2 enhanced it. Taken together, our results suggest that Sprouty2 regulates GDNF-dependent proliferation and differentiation of TGW neuroblastoma cells mediated by RET tyrosine kinase. These results have been reported in Cancer Science (Cancer Sci 98: 815-821, 2007). We next generated double knocli-out and knock-in mice between mutant RET (Y1062F) and Sprouty2 and observed their phenotype especially in the enteric nervous system and the kidney. Sprouty2-defficient mice demonstrated increased number of enteric neurons and achalasia-like dilution of esophagus, whereas Sprouty2 deficiency did not affect nephrogenesis even though high expression of Sprouty2 in the kidney. In contrast, mice with homozygous mutant RET demonstrated the decreased number of enteric neurons and small kidneys accompanying histological change. Interesting, Sprouty2 deficiency partially rescued the abnormal phenotype both in the enteric nervous system and nephrogenesis in homozygous RET mutant mice. These results suggest that Sprouty2 actually modulates the downstream signaling of RET tyrosine kinase and regulates mouse organogenesis in vivo. Less