title: Sprouty2 regulates growth and differentiation of human neuroblastoma cells through RET tyrosine kinase.
abstract: The Sprouty (SPRY) family of proteins includes important regulators of downstream signaling initiated by receptor tyrosine kinases. In the present study, we investigated the role of SPRY proteins in intracellular signaling via the RET receptor tyrosine kinase activated by glial cell line-derived neurotrophic factor (GDNF). Expression of SPRY1, SPRY2, SPRY3 and SPRY4 in HEK293T cells transfected with RET and GDNF receptor family alpha1 (GFRalpha1) genes significantly reduced sustained ERK activation as well as ELK-1 activation. Because expression of SPRY2 was efficiently induced by GDNF in TGW human neuroblastoma cells expressing RET and GFRalpha1, we further investigated the role of SPRY2 in the growth and differentiation of TGW cells. Expression of wild-type SPRY2 (WT-SPRY2) decreased the growth of TGW cells. In contrast, expression of a dominant negative form of SPRY2 (MT-SPRY2, with a mutated tyrosine residue) enhanced cell proliferation. In addition, expression of WT-SPRY2 reduced GDNF-dependent neurite outgrowth of TGW cells, whereas expression of MT-SPRY2 enhanced it. Taken together, our results suggest that SPRY2 regulates GDNF-dependent proliferation and differentiation of TGW neuroblastoma cells mediated by RET tyrosine kinase.
authors: Department of Pathology, and Department of Mrfovs; Technology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Maki
authors: M
authors: Ishida
authors: Masatoshi
authors: M
authors: Ichihara
authors: Shinji
authors: S
authors: Mii
authors: Mayumi
authors: M
authors: Jijiwa
authors: Naoya
authors: N
authors: Asai
authors: Atsushi
authors: A
authors: Enomoto
authors: Takuya
authors: T
authors: Kato
authors: Ai
authors: A
authors: Majima
authors: Jiang
authors: J
authors: Ping
authors: Yoshiki
authors: Y
authors: Murakumo
authors: Masahide
authors: M
authors: Takahashi
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism; D008565:Membrane Proteins; D016501:Neurites / Q000187:drug effects; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C485561:SPRY2 protein, human; D051096:Proto-Oncogene Proteins c-ret; D048748:MAP Kinase Kinase Kinase 3