Open AccessVLA-4 phosphorylation during tumor and immune cell migration relies on its coupling to VEGFR2 and CXCR4 by syndecan-1
Author(s) -
Oisun Jung,
DeannaLee M. Beauvais,
Kristin M. Adams,
Alan C. Rapraeger
Publication year - 2019
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.232645
Subject(s) - biology , phosphorylation , microbiology and biotechnology , cancer research , motility , integrin , cytotoxic t cell , receptor , biochemistry , in vitro
Syndecan-1 shed when targeted by the tumor-promoting enzyme heparanase couples VEGFR2 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/CXCL12. The entire machinery necessary to phosphorylate VLA-4, consisting of CXCR4, adenylate cyclase 7 (AC7) and PKA, is constitutively associated with VEGFR2 and is localized to the integrin by Sdc1. VEGFR2 carries out the novel phosphorylation of Y135 within CXCR4's DRY microswitch, 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.