Protein kinase B (AKT) regulates SYK activity and shuttling through 14-3-3 and importin 7
| Autor: | C. I. Edvard Smith, Dara K. Mohammad, Abdalla J. Mohamed, Manuela O. Gustafsson, Beston F. Nore |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cytoplasm Proto-Oncogene Proteins c-akt Amino Acid Motifs Receptors Cytoplasmic and Nuclear Syk Karyopherins environment and public health Biochemistry 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor hemic and lymphatic diseases Chlorocebus aethiops Akt Inhibitor MK2206 Animals Humans Syk Kinase Bruton's tyrosine kinase Phosphorylation Protein kinase B Adaptor Proteins Signal Transducing PHLPP biology hemic and immune systems Tyrosine phosphorylation Cell Biology Cell biology enzymes and coenzymes (carbohydrates) 030104 developmental biology 14-3-3 Proteins chemistry COS Cells Cancer research biology.protein |
| Zdroj: | The International Journal of Biochemistry & Cell Biology. 78:63-74 |
| ISSN: | 1357-2725 |
| DOI: | 10.1016/j.biocel.2016.06.024 |
| Popis: | The Protein kinase B (AKT) regulates a plethora of intracellular signaling proteins to fine-tune signaling of multiple pathways. Here, we found that following B-cell receptor (BCR)-induced tyrosine phosphorylation of the cytoplasmic tyrosine kinase SYK and the adaptor BLNK, the AKT/PKB enzyme strongly induced BLNK (>100-fold) and SYK (>100-fold) serine/threonine phosphorylation (pS/pT). Increased phosphorylation promoted 14-3-3 binding to BLNK (37-fold) and SYK (2.5-fold) in a pS/pT-concentration dependent manner. We also demonstrated that the AKT inhibitor MK2206 reduced pS/pT of both BLNK (3-fold) and SYK (2.5-fold). Notably, the AKT phosphatase, PHLPP2 maintained the activating phosphorylation of BLNK at Y84 and increased protein stability (8.5-fold). In addition, 14-3-3 was required for the regulation SYK's interaction with BLNK and attenuated SYK binding to Importin 7 (5-fold), thereby perturbing shuttling to the nucleus. Moreover, 14-3-3 proteins also sustained tyrosine phosphorylation of SYK and BLNK. Furthermore, substitution of S295 or S297 for alanine abrogated SYK's binding to Importin 7. SYK with S295A or S297A replacements showed intense pY525/526 phosphorylation, and BLNK pY84 phosphorylation correlated with the SYK pY525/526 phosphorylation level. Conversely, the corresponding mutations to aspartic acid in SYK reduced pY525/526 phosphorylation. Collectively, these and previous results suggest that AKT and 14-3-3 proteins down-regulate the activity of several BCR-associated components, including BTK, BLNK and SYK and also inhibit SYK's interaction with Importin 7. |
| Databáze: | OpenAIRE |
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