The interplay of CD150 and CD180 receptor pathways contribute to the pathobiology of chronic lymphocytic leukemia B cells by selective inhibition of Akt and MAPK signaling
| Autor: | Edward A. Clark, Svetlana P. Sidorenko, Valeriia Kholodniuk, D F Gluzman, L. M. Shlapatska, L M Sklyarenko, I M Gordiienko |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cell signaling Cytoplasm B Cells Chronic lymphocytic leukemia Protein Expression Gene Expression lcsh:Medicine Cell Separation mTORC1 Immune Receptors Biochemistry Hematologic Cancers and Related Disorders White Blood Cells Signaling Lymphocytic Activation Molecule Family Member 1 Animal Cells hemic and lymphatic diseases Medicine and Health Sciences Post-Translational Modification Phosphorylation B Cell Receptors Receptor lcsh:Science Chronic Lymphoblastic Leukemia B-Lymphocytes Immune System Proteins Multidisciplinary biology Chemistry Signaling cascades Hematology Flow Cytometry Cell biology Oncology Lymphoblastic Leukemia Cellular Types Cellular Structures and Organelles Signal transduction Research Article Signal Transduction MAPK signaling cascades MAP Kinase Signaling System Immune Cells Immunology B-cell receptor Research and Analysis Methods 03 medical and health sciences Antigens CD Leukemias Genetics Gene Expression and Vector Techniques medicine Humans Antibody-Producing Cells Molecular Biology Techniques Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Molecular Biology Assays and Analysis Techniques Blood Cells CD40 lcsh:R Biology and Life Sciences Proteins Cancers and Neoplasms Cell Biology medicine.disease Leukemia Lymphocytic Chronic B-Cell 030104 developmental biology biology.protein lcsh:Q Proto-Oncogene Proteins c-akt |
| Zdroj: | PLoS ONE, Vol 12, Iss 10, p e0185940 (2017) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Cell surface expression of CD150 and CD180 receptors in chronic lymphocytic leukemia (CLL) associates with mutational IGHV status and favourable prognosis. Here we show a direct correlation between cell surface expression and colocalization of these receptors on CLL B cells. In the absence of CD150 and CD180 on the cell surface both receptors were expressed in the cytoplasm. The CD150 receptor was colocalized with markers of the endoplasmic reticulum, the Golgi apparatus and early endosomes. In contrast, CD180 was detected preferentially in early endosomes. Analysis of CD150 isoforms differential expression revealed that regardless of CD150 cell surface expression the mCD150 isoform with two ITSM signaling motifs was a predominant CD150 isoform in CLL B cells. The majority of CLL cases had significantly elevated expression level of the soluble sCD150, moreover CLL B cells secrete this isoform. CD150 or CD180 crosslinking on CLL B cells alone led to activation of Akt, mTORC1, ERK1/2, p38MAPK and JNK1/2 networks. Both CD150 and CD180 target the translation machinery through mTOR independent as well as mTOR dependent pathways. Moreover, both these receptors transmit pro-survival signals via Akt-mediated inhibition of GSK3β and FOXO1/FOXO3a. Unexpectedly, coligation CD150 and CD180 receptors on CLL B cells led to mutual inhibition of the Akt and MAPK pathways. While CD150 and CD180 coligation resulted in reduced phosphorylation of Akt, ERK1/2, c-Jun, RSK, p70S6K, S6RP, and 4E-BP; it led to complete blocking of mTOR and p38MAPK phosphorylation. At the same time coligation of CD150 and CD40 receptors did not result in Akt and MAPK inhibition. This suggests that combination of signals via CD150 and CD180 leads to blocking of pro-survival pathways that may be a restraining factor for neoplastic CLL B cells propagation in more than 50% of CLL cases where these receptors are coexpressed. |
| Databáze: | OpenAIRE |
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