摘要
血液中白细胞被血管内皮细胞捕获、沿着血管内皮细胞滚动、稳定粘附于血管内皮细胞上、跨血管内皮细胞迁移并最终到达炎症部位是一个受严格调控的复杂多步骤的过程。至少有三类粘附分子家族在这一过程中发挥重要作用,其中选择素家族分子主要参与了白细胞捕获和沿血管内皮细胞上的滚动过程。L-选择素是选择素家族成员之一,组成性地表达在白细胞微绒毛顶端,是白细胞与血管内皮细胞相互作用过程中最先行使功能的分子。除了作为粘附分子发挥作用,L-选择素还作为信号分子在白细胞粘附过程中起始信号转导过程。L-选择素与单克隆抗体的结合能够引起肌动蛋白细胞骨架重排、细胞形态改变、氧呼吸爆发以及细胞内TNF-α和IL-8基因表达上调等一系列生理事件。但L-选择素是如何利用胞内蛋白传递信号并引发一系列生理变化的,其具体机制仍不清楚。Lck激酶是非受体蛋白酪氨酸激酶Src家族的成员之一,特异性地在T淋巴细胞中表达,并且在T淋巴细胞的活化及发育过程中发挥着重要作用。L-选择素与其单克隆抗体的交联能够活化Lck激酶,我们推测,Lck激酶不仅参与了L-选择素信号转导,并在其中发挥关键性作用。本文主要探讨了Lck激酶是如何调控sulfatides交联L-选择素后引起的信号转导过程的。
我们发现,在Jurkat T细胞中,sulfatides与L-选择素的交联能够引起Lck激酶快速强烈的酪氨酸磷酸化,而且Lck激酶的特异性抑制剂PP2不仅阻断了L-选择素交联引起的肌动蛋白细胞骨架重排过程,而且还显著抑制了L-选择素介导的Jurkat T细胞在人脐静脉内皮细胞上的滚动,说明Lck激酶不仅位于L-选择素信号转导通路中,而且对于L-选择素信号的传递起着关键性作用。通过与L-选择素胞浆尾部的直接结合,Lck激酶能够在活化之后快速地磷酸化L-选择素胞浆尾部,增强L-选择素信号。L-选择素胞浆尾部唯一的酪氨酸位点,Tyr372,在L-选择素与Lck激酶的直接结合中发挥重要作用,因为这一位点的突变显著抑制了二者的结合。在sulfatides交联一段时间后,L-选择素与Lck激酶的结合能力减弱,也就是说这个时候的Lck激酶已经开始从L-选择素的胞浆尾部解离。我们认为,正是由于这种蛋白结合的动态性,才使得L-选择素能够通过其只有17个氨基酸的胞浆尾部与多种胞内信号蛋白结合,传递多种信号。
通过其SH3和SH2结构域与c-Abl激酶和ZAP-70激酶的直接结合,Lck激酶在L-选择素胞浆尾部形成了一个大的信号转导复合体。在L-选择素交联活化后,Lck激酶先于c-Abl激酶活化。Lck激酶的特异性抑制剂PP2能够显著抑制c-Abl激酶的磷酸化水平和激酶活性,同时明显降低ZAP-70激酶的整体和Tyr319酪氨酸磷酸化水平,甚至连本底水平也都受到影响。而c-Abl激酶的特异性抑制剂STI571与ZAP-70激酶的特异性抑制剂Piceatannol则对Lck激酶的磷酸化没有任何作用。这些结果说明,在L-选择素信号转导途径中,Lck激酶是最先被活化的激酶,并通过影响下游c-Abl激酶和ZAP-70激酶的活性而传递L-选择素信号。
当干涉胞内Lck激酶表达后,L-选择素信号被显著抑制。不仅L-选择素、c-Abl激酶和ZAP-70激酶的酪氨酸磷酸化水平明显降低,细胞在人脐静脉内皮细胞上的滚动也相应地受到影响。转入野生型或激酶永久活化型而非激酶永久失活型鼠Lck表达质粒能够补偿内源Lck激酶干涉造成的蛋白磷酸化水平缺失和细胞滚动减少,说明Lck激酶的激酶活性对于L-选择素信号转导是十分重要的。SH2结构域突变型质粒不能够恢复细胞内蛋白磷酸化的水平,但却部分地补偿细胞滚动减少,而SH3结构域突变型质粒的作用却正好相反,这些结果说明Lck激酶的SH3和SH2结构域行使不同的信号转导功能。
本文结果表明,在L-选择素交联引起的信号转导事件中,Lck激酶起到了关键性的作用。它不仅通过与L-选择素胞浆尾部的直接结合,接受并增强L-选择素信号,还能通过与行使不同信号转导功能的SH3和SH2结构域与下游c-Abl激酶和ZAP-70激酶直接结合,进而将L-选择素信号快速有效地向下游传递。同时,与Lck激酶的动态结合使得L-选择素胞浆尾部能够在Lck激酶从其胞浆尾部解离下来后结合其他的胞内蛋白,促进L-选择素信号沿其它信号转导途径传递。
Leukocyte recruitment from the bloodstream to a site of inflammation entails a cascade of cellular adhesive events, including tethering, rolling, adhesion and transmigration. This process is controlled strictly by three families of adhesive molecules expressed on leukocytes and endothelial cells, and selectin family is responsible for the initial tethering and rolling of leukocytes. As a member of selectin family, L-selectin constitutively expresses on the top of microvilli and appears to be the first receptor for the early kinetics of leukocyte-endothelial cell interaction. Besides, L-selectin contributes in leukocyte adhesion through its signaling properties. L-selectin engagement with antibody cross-linking could trigger actin cytoskeleton rearrangement, cell shape change, superoxide generation, increased gene expression of cytokine TNF-αand IL-8, and so on. We still do not know how L-selectin orchestrates those cytoplasmic proteins to transduce signals. Lck kinase is a member of the Src family of non-receptor protein tyrosine kinases, which is expressed primarily in T lymphocytes and plays an important role in T cell activation and development. Cross-linking L-selectin with antibody induces the activation of Lck kinase, so we suppose that Lck kinase not only is involved in L-selectin signaling, but also plays a critical role in the process. In this paper, we focus on the Lck kinase function in regulating L-selectin signaling induced by sulfatides engagement.
In Jurkat T cells, we find that L-selectin ligation with sulfatides induces rapid and robust tyrosine phosphorylation of Lck kinase, while PP2 (Lck specific inhibitor) significantly inhibits actin cytoskeleton rearrangement induced by L-selectin engagement and L-selectin-mediated Jurkat T cell rolling on HUVECs (human umbilical vein endothelial cells). These results suggest Lck kinase is involved in L-selectin signaling and plays an important role. Through the direct interaction with L-selectin cytoplasmic tail, activated Lck kinase could phosphorylate cytoplasmic tail in a minute promoting signal transduction. The only tyrosine, Tyr372, of cytoplasmic tail of L-selectin has an effect on the direct interaction with Lck kinase, for its mutation dramatically inhibits this association. After sulfatides stimulation for 2 min, the interaction between L-selectin and Lck kinase attenuates, suggesting that Lck kinase detaches from L-selectin cytoplasmic tail. For the dynamics of interaction, L-selectin could bind different cytosolic signaling proteins using its cytoplasmic tail composed of 17 amino acids.
Through the direct interaction with c-Abl and ZAP-70 kinases via its SH3 and SH2 domains, Lck kinase organizes a signaling complex at the cytoplasmic tail of L-selectin. After sulfatides engagement, Lck kinase activated prior to c-Abl kinase. PP2 (Lck specific inhibitor) could dramatically inhibit the phosphorylation and kinase activity of c-Abl kinase, which also nearly completely decreased the phosphorylation of total and Tyr319 of ZAP-70 kinase. STI571 (c-Abl specific inhibitor) and Piceatannol (ZAP-70 specific inhibitor) play no role on the phosphorylation of Lck kinase. These results indicate that Lck kinase is the first kinase to be activated and regulate the kinase activity of both c-Abl and ZAP-70 kinases in L-selectin signaling pathway.
In the cells with Lck knockdown by siRNA treatment, L-selectin signaling is severely suppressed, as indicated by reduced phosphorylation of L-selectin, c-Abl kinase and ZAP-70 kinase and by decreased number of Jurkat T cell rolling on HUVECs. Re-expression of wild-type or constitutively active but not kinase-dead murine Lck completely rescue the phosphorylation, suggesting the kinase activity of Lck is important for L-selectin signaling. Re-expression of SH2 domain mutant has no effect on protein phosphorylation but partly rescues the cell rolling, while re-expression of SH3 domain mutant has the opposite role, indicating that SH2 and SH3 domains of Lck kinase perform different signaling functions.
In summary, Lck kinase plays a critical role in L-selectin signaling induced by sulfatides engagement. Through the direct interaction with L-selectin cytoplasmic tail, Lck kinase accepts and amplifies L-selectin signal. On the other hand, Lck kinase transduces signals quickly and efficiently by binding c-Abl and ZAP-70 kinases via its SH3 and SH2 domains. Meanwhile, because of the dynamic interaction with Lck kinase, L-selectin could bind other cytosolic proteins to transducer signals in other signaling pathway.
引文
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