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.

中文翻译：

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肿瘤和免疫细胞迁移过程中VLA-4的磷酸化依赖于syndecan-1与VEGFR2和CXCR4的偶联。

当被促肿瘤酶乙酰肝素酶靶向时，裂解并脱落的syndecan-1（Sdc1）然后将VEGFR2（也称为KDR）与VLA-4偶联，激活VEGFR2和骨髓瘤细胞的定向迁移。但是，VEGFR2如何激活VLA-4介导的运动性仍然未知。现在我们报道，VEGFR2引起S988上PLA介导的VLA-4磷酸化，该事件已知可刺激肿瘤转移，同时抑制细胞毒性免疫细胞。该机制的关键伙伴是趋化因子受体CXCR4，它是对趋化因子SDF-1（也称为CXCL12）的梯度作出反应的细胞运动的众所周知的介质。磷酸化VLA-4所需的整个机械（包括CXCR4，AC7（也称为ADCY7）和PKA）与VEGFR2组成性结合，并由Sdc1定位于整联蛋白。VEGFR2在CXCR4的DRY微开关内执行Y135的新型磷酸化，依次激活Gαiβγ，AC7和PKA，从而使整联蛋白上的S988磷酸化。该机制被同聚糖模拟肽（SSTNVEGFR2）阻断，该合成肽通过阻止VEGFR2与VLA-4的连接，阻止依赖于VLA-4磷酸化的肿瘤细胞迁移并刺激LFA-1介导的细胞毒性白细胞迁移。