TY - JOUR
T1 - The c-Fes protein-tyrosine kinase accelerates NGF-induced differentiation of PC12 cells through a PI3K-dependent mechanism
AU - Shibata, Annemarie
AU - Laurent, Charles E.
AU - Smithgall, Thomas E.
N1 - Funding Information:
The authors wish to thank Dr. Peter Greer of Queen's University, Ontario, Canada, for the generous gift of the Fps/Fes and Fer antisera. This work was supported by National Institutes of Health grant CA58667 to T.E.S.
PY - 2003/3/1
Y1 - 2003/3/1
N2 - The c-fes protooncogene encodes a non-receptor protein-tyrosine kinase (Fes) that has been implicated in the differentiation of myeloid haematopoietic cells. Fes is also expressed in several neuronal cell types and the vascular endothelium, suggestive of a more general function in development. To examine the role of Fes in neuronal differentiation, we investigated the effect of Fes expression on process outgrowth in PC12 cells following stimulation with nerve growth factor (NGF). PC12 cells expressing wild-type and activated mutants of Fes extended processes faster and of greater length than control cells. In contrast, expression of kinase-inactive Fes was without effect, indicating that cooperation with NGF requires Fes kinase activity. Short-term treatment of PC12-Fes cells with NGF enhanced tyrosine phosphorylation of Fes, suggesting upstream regulation by the NGF receptor. Fes-mediated acceleration of neurite outgrowth was blocked by wortmannin and LY294002, implicating phosphatidylinositol 3-kinase (PI3K) activation in the Fes-induced response. In contrast, the MEK inhibitor PD98059 was without effect, suggesting that the Ras-Erk pathway is not involved. These data provide the first evidence that Fes may contribute to morphological differentiation of neuronal cells by enhancing NGF signalling through the PI3K pathway.
AB - The c-fes protooncogene encodes a non-receptor protein-tyrosine kinase (Fes) that has been implicated in the differentiation of myeloid haematopoietic cells. Fes is also expressed in several neuronal cell types and the vascular endothelium, suggestive of a more general function in development. To examine the role of Fes in neuronal differentiation, we investigated the effect of Fes expression on process outgrowth in PC12 cells following stimulation with nerve growth factor (NGF). PC12 cells expressing wild-type and activated mutants of Fes extended processes faster and of greater length than control cells. In contrast, expression of kinase-inactive Fes was without effect, indicating that cooperation with NGF requires Fes kinase activity. Short-term treatment of PC12-Fes cells with NGF enhanced tyrosine phosphorylation of Fes, suggesting upstream regulation by the NGF receptor. Fes-mediated acceleration of neurite outgrowth was blocked by wortmannin and LY294002, implicating phosphatidylinositol 3-kinase (PI3K) activation in the Fes-induced response. In contrast, the MEK inhibitor PD98059 was without effect, suggesting that the Ras-Erk pathway is not involved. These data provide the first evidence that Fes may contribute to morphological differentiation of neuronal cells by enhancing NGF signalling through the PI3K pathway.
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U2 - 10.1016/S0898-6568(02)00089-X
DO - 10.1016/S0898-6568(02)00089-X
M3 - Article
C2 - 12531426
AN - SCOPUS:0037340142
SN - 0898-6568
VL - 15
SP - 279
EP - 288
JO - Cellular Signalling
JF - Cellular Signalling
IS - 3
ER -