VLA-4 phosphorylation during tumor and immune cell migration relies on its coupling to VEGFR2 and CXCR4 by syndecan-1
| Autor: | Oisun Jung, DeannaLee M. Beauvais, Alan C. Rapraeger, Kristin M. Adams |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Chemokine
Receptors CXCR4 Integrin Motility Integrin alpha4beta1 Syndecan 1 03 medical and health sciences Chemokine receptor 0302 clinical medicine Cell Movement Cell Line Tumor Neoplasms Cytotoxic T cell Humans Phosphorylation Immunologic Surveillance 030304 developmental biology 0303 health sciences biology VLA-4 Cell Biology respiratory system Vascular Endothelial Growth Factor Receptor-2 Cell biology Neoplasm Proteins biology.protein cardiovascular system Syndecan-1 030217 neurology & neurosurgery circulatory and respiratory physiology Research Article |
| Zdroj: | J Cell Sci |
| ISSN: | 1477-9137 |
| Popis: | When targeted by the tumor-promoting enzyme heparanase, cleaved and shed syndecan-1 (Sdc1) then couples VEGFR2 (also known as KDR) to VLA-4, activating VEGFR2 and the directed migration of myeloma cells. But how VEGFR2 activates VLA-4-mediated motility has remained unknown. We now report that VEGFR2 causes PKA-mediated phosphorylation of VLA-4 on S988, an event known to stimulate tumor metastasis while suppressing cytotoxic immune cells. A key partner in this mechanism is the chemokine receptor CXCR4, a well-known mediator of cell motility in response to gradients of the chemokine SDF-1 (also known as CXCL12). The entire machinery necessary to phosphorylate VLA-4, consisting of CXCR4, AC7 (also known as ADCY7) and PKA, is constitutively associated with VEGFR2 and is localized to the integrin by Sdc1. VEGFR2 carries out the novel phosphorylation of Y135 within the DRY microswitch of CXCR4, sequentially activating Gαiβγ, AC7 and PKA, which phosphorylates S988 on the integrin. This mechanism is blocked by a syndecan-mimetic peptide (SSTNVEGFR2), which, by preventing VEGFR2 linkage to VLA-4, arrests tumor cell migration that depends on VLA-4 phosphorylation and stimulates the LFA-1-mediated migration of cytotoxic leukocytes. |
| Databáze: | OpenAIRE |
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