Sprouty2 regulates growth and differentiation of human neuroblastoma cells through RET tyrosine kinase.
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.
Ishida
Maki
M
Department of Pathology, and Department of Mrfovs; Technology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Ichihara
Masatoshi
M
Mii
Shinji
S
Jijiwa
Mayumi
M
Asai
Naoya
N
Enomoto
Atsushi
A
Kato
Takuya
T
Majima
Ai
A
Ping
Jiang
J
Murakumo
Yoshiki
Y
Takahashi
Masahide
M
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
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