Phosphorylation of the cytoplasmic tail of syndecan-4 regulates activation of protein kinase Cα
Phosphorylation of the cytoplasmic tail of syndecan-4 regulates activation of protein kinase Cα
复制标题
DOI：
10.1074/jbc.273.40.25548
复制
发表时间：
1998-10-02
影响因子：
4.8
通讯作者：
Simons, M
中科院分区：
文献类型：
--
作者：
Horowitz, A;Simons, M
Syndecans是一种跨膜蛋白聚糖，能够同时携带肝素和硫酸软骨素链。最近有报道称syndecan-4的胞质尾部在其尾部近端膜处的Ser（183）发生了体内磷酸化(Horowitz， A., and Simons， M.（1998）。化学学报，23(3),391 - 398。然而，这一事件的功能后果仍然未知。syndecan-4的细胞质尾部已知经历多聚并激活蛋白激酶C α (PKC α)，这两个事件取决于常见的磷脂磷脂酰肌醇4,5-二磷酸（PIP2）的存在。在目前的研究中，我们发现Ser（183）的磷酸化使syndecan-4激活PKC α的能力降低了10倍，而不影响其结合PKC的能力。由于Ser（183）邻近带正电荷的赖氨酸基团，与其他几种蛋白质中的PIP2结合区相似，因此该丝氨酸的磷酸化可能会影响syndecan-4细胞质尾部与PIP2的结合亲和力。我们发现，与非磷酸化尾部相比，syndecan-4的Ser（183）磷酸化的细胞质尾部对PIP2的亲和力确实显著降低。此外，Ser（183）磷酸化可消除syndecan-4细胞质尾部的pip2依赖性寡聚化。我们得出结论，Ser（183）磷酸化通过降低对PIP2的亲和力和抑制syndecan-4细胞质尾部的寡聚化来调节syndecan-4依赖性PKC α的激活。这些结果进一步支持了syndecan-4在内皮细胞信号转导中的作用。
Syndecans are transmembrane proteoglycans capable of carrying both heparan and chondroitin sulfate chains. The cytoplasmic tail of syndecan-4 was recently reported to undergo in vivo phosphorylation on Ser(183) in the membrane-proximal part of the tail (Horowitz, A., and Simons, M. (1998) J. Biol. Chem. 273, 10914-10918). However, the functional consequences of this event remain unknown. The cytoplasmic tail of syndecan-4 is known to undergo multimerization and to activate protein kinase C alpha (PKC alpha), with both events depending on the presence of the commonly occurring phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). In the present investigation we found that phosphorylation of Ser(183) produced a 10-fold reduction in the ability of syndecan-4 to activate PKC alpha, without affecting its ability to bind the PKC. Because Ser(183) is adjacent to positively charged lysine groups that resemble PIP2-binding regions in several other proteins, phosphorylation of this serine may affect the binding affinity of the syndecan-4 cytoplasmic tail to PIP2. We found that the Ser(183)-phosphorylated cytoplasmic tail of syndecan-4 has indeed a significantly lower affinity to PIP2 compared with the nonphosphorylated tail. Furthermore, Ser(183) phosphorylation abolished PIP2-dependent oligomerization of syndecan-4 cytoplasmic tails. We conclude that Ser(183) phosphorylation regulates syndecan-4-dependent activation of PKC alpha by reducing the affinity to PIP2 and inhibiting the oligomerization of syndecan-4 cytoplasmic tails. These results further support the role of syndecan-4 in signal transduction in endothelial cells.