TY - JOUR
T1 - PKA phosphorylation and 14-3-3 interaction regulate the function of neurofibromatosis type I tumor suppressor, neurofibromin
AU - Feng, Liping
AU - Yunoue, Shunji
AU - Tokuo, Hiroshi
AU - Ozawa, Tatsuya
AU - Zhang, Dongwei
AU - Patrakitkomjorn, Siriporn
AU - Ichimura, Toru
AU - Saya, Hideyuki
AU - Araki, Norie
N1 - Funding Information:
We would like to thank Y. Fukushima for secretarial assistance. This work was supported by grants from the Ministry of Health and Welfare of Japan (H.S.), Brain Research (N.A.), Cancer Research (N.A.) from Ministry of Education, Culture, Sports, Science and Technology of Japan, and Kiban Research from the Japan Society for the Promotion of Science (N.A.).
PY - 2004/1/16
Y1 - 2004/1/16
N2 - Neurofibromin, a neurofibromatosis type I (NF1) tumor suppressor gene product, has a domain acting as a GTPase activating protein and functions in part as a negative regulator of Ras. Loss of neurofibromin expression in NF1 patients is associated with elevated Ras activity and increased cell proliferation. Therefore, regulation of the function of neurofibromin is heavily involved in cell growth and differentiation. In the present study, we identified a novel cellular neurofibromin-associating protein, 14-3-3, which belongs to a highly conserved family of proteins that regulate intracellular signal transduction events in all eukaryotic cells. The interaction of 14-3-3 is mainly directed to the C-terminal domain (CTD) of neurofibromin, and the cAMP-dependent protein kinase (PKA)-dependent phosphorylation clustered on CTD-Ser (2576, 2578, 2580, 2813) and Thr (2556) is required for the interaction. Interestingly, the increased phosphorylation and association of 14-3-3 negatively regulate the function of neurofibromin. These findings indicate that PKA phosphorylation followed by 14-3-3 protein interaction may modulate the biochemical and biological functions of neurofibromin.
AB - Neurofibromin, a neurofibromatosis type I (NF1) tumor suppressor gene product, has a domain acting as a GTPase activating protein and functions in part as a negative regulator of Ras. Loss of neurofibromin expression in NF1 patients is associated with elevated Ras activity and increased cell proliferation. Therefore, regulation of the function of neurofibromin is heavily involved in cell growth and differentiation. In the present study, we identified a novel cellular neurofibromin-associating protein, 14-3-3, which belongs to a highly conserved family of proteins that regulate intracellular signal transduction events in all eukaryotic cells. The interaction of 14-3-3 is mainly directed to the C-terminal domain (CTD) of neurofibromin, and the cAMP-dependent protein kinase (PKA)-dependent phosphorylation clustered on CTD-Ser (2576, 2578, 2580, 2813) and Thr (2556) is required for the interaction. Interestingly, the increased phosphorylation and association of 14-3-3 negatively regulate the function of neurofibromin. These findings indicate that PKA phosphorylation followed by 14-3-3 protein interaction may modulate the biochemical and biological functions of neurofibromin.
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U2 - 10.1016/S0014-5793(03)01507-2
DO - 10.1016/S0014-5793(03)01507-2
M3 - Article
C2 - 14741381
AN - SCOPUS:1642573162
SN - 0014-5793
VL - 557
SP - 275
EP - 282
JO - FEBS Letters
JF - FEBS Letters
IS - 1-3
ER -