The Tandem PH Domain-Containing Protein 2 (TAPP2) Regulates Chemokine-Induced Cytoskeletal Reorganization and Malignant B Cell Migration
| Autor: | Saravanan Nandagopal, Aaron J. Marshall, Xun Wu, Sam Kung, Sen Hou, Hongzhao Li, Francis Lin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
B Cells
Polyphosphoinositide Signaling Cascade Lymphoma Utrophin lcsh:Medicine Hematologic Cancers and Related Disorders 0302 clinical medicine Bone Marrow Cell Movement Molecular Cell Biology Signaling in Cellular Processes lcsh:Science Cytoskeleton 0303 health sciences B-Lymphocytes Multidisciplinary Leukemia Intracellular Signaling Peptides and Proteins Signal transducing adaptor protein Cell migration Hematology Flow Cytometry Cellular Structures Signaling Cascades Cell biology rac GTP-Binding Proteins Actin Cytoskeleton Protein Transport medicine.anatomical_structure 030220 oncology & carcinogenesis Gene Knockdown Techniques Medicine Lymphomas Cell Movement Signaling Intracellular Research Article Signal Transduction Stromal cell Immune Cells Immunology Phosphoinositide Signal Transduction Biology Signaling Pathways 03 medical and health sciences Leukemias medicine Humans PI3K/AKT/mTOR pathway B cell 030304 developmental biology lcsh:R Membrane Proteins Mesenchymal Stem Cells Actin cytoskeleton Actins Chemokine CXCL12 Immune System lcsh:Q Cytometry |
| Zdroj: | PLoS ONE PLoS ONE, Vol 8, Iss 2, p e57809 (2013) |
| ISSN: | 1932-6203 |
| Popis: | The intracellular signaling processes controlling malignant B cell migration and tissue localization remain largely undefined. Tandem PH domain-containing proteins TAPP1 and TAPP2 are adaptor proteins that specifically bind to phosphatidylinositol-3,4-bisphosphate, or PI(3,4)P2, a product of phosphoinositide 3-kinases (PI3K). While PI3K enzymes have a number of functions in cell biology, including cell migration, the functions of PI(3,4)P2 and its binding proteins are not well understood. Previously we found that TAPP2 is highly expressed in primary leukemic B cells that have strong migratory capacity. Here we find that SDF-1-dependent migration of human malignant B cells requires both PI3K signaling and TAPP2. Migration in a transwell assay is significantly impaired by pan-PI3K and isoform-selective PI3K inhibitors, or by TAPP2 shRNA knockdown (KD). Strikingly, TAPP2 KD in combination with PI3K inhibitor treatment nearly abolished the migration response, suggesting that TAPP2 may contribute some functions independent of the PI3K pathway. In microfluidic chamber cell tracking assays, TAPP2 KD cells show reduction in percentage of migrating cells, migration velocity and directionality. TAPP2 KD led to alterations in chemokine-induced rearrangement of the actin cytoskeleton and failure to form polarized morphology. TAPP2 co-localized with the stable F-actin-binding protein utrophin, with both molecules reciprocally localizing against F-actin accumulated at the leading edge upon SDF-1 stimulation. In TAPP2 KD cells, Rac was over-activated and localized to multiple membrane protrusions, suggesting that TAPP2 may act in concert with utrophin and stable F-actin to spatially restrict Rac activation and reduce formation of multiple membrane protrusions. TAPP2 function in cell migration is also apparent in the more complex context of B cell migration into stromal cell layers - a process that is only partially dependent on PI3K and SDF-1. In summary, this study identified TAPP2 as a novel regulator of malignant B cell migration and a potential therapeutic intervention target. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|