PKA phosphorylation and 14‐3‐3 interaction regulate the function of neurofibromatosis type I tumor suppressor, neurofibromin

FEBS Letters

Araki, Norie²  Ichimura, Toru¹  Feng, Liping²  Yunoue, Shunji²  Ozawa, Tatsuya²  Zhang, Dongwei²  Patrakitkomjorn, Siriporn²  Tokuo, Hiroshi²  Saya, Hideyuki² 

[1] Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Hachioji-shi, Tokyo 192-0397, Japan;Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan

关键词: Neurofibromatosis type I;    Neurofibromin;    cAMP-dependent protein kinase;    Tumor suppressor;    14-3-3 protein;    GTPase activating protein;    NF1;    neurofibromatosis type I;    GAP;    GTPase-activity protein;    PKA;    cAMP-dependent protein kinase;    CSRD;    cysteine/serine-rich domain;    CTD;    C-terminal domain;    GRD;    GAP-related domain;   

DOI  :  10.1016/S0014-5793(03)01507-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown