Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells
Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells
复制标题
DOI：
10.1038/sj.leu.2404769
复制
发表时间：
2007-08-01
期刊：
影响因子：
11.4
通讯作者：
Silberstein, L. E.
中科院分区：
文献类型：
--
作者：
Glodek, A. M.;Le, Y.;Silberstein, L. E.
造血干/祖细胞（HSC/P）位于骨髓中不同的解剖位置（小生境）以接收生长、存活和分化信号。HSC/P的定位和迁移依赖于细胞与细胞、细胞与基质之间的相互作用，这些相互作用是细胞因子、趋化因子和粘附分子共同作用的结果。CXCL 12-CXCR 4通路对于骨髓生成和B淋巴细胞生成尤其重要，但CXCL 12作用的分子机制仍不清楚。我们以前注意到，在祖B细胞中，CXCL 12介导的粘着斑激酶（FAK）磷酸化延长与持续的促粘附反应之间存在强相关性，但在成熟B细胞中不存在。虽然FAK在贴壁成纤维细胞中已被充分研究，但其在造血细胞中的功能尚未确定。我们使用了两种独立的方法来减少（人和小鼠）祖细胞中FAK的表达。RNA干扰（RNAi）介导的FAK沉默消除了人pro-B白血病REH细胞中CXCL 12诱导的反应。FAK缺陷的REH细胞也表现出减少CXCL 12诱导的GTdR Rap 1活化，表明FAK在CXCL 12介导的整合素活化中的重要性。此外，在FAK（flox/flox）造血前体细胞中，Cre介导的FAK缺失导致CXCL 12诱导的趋化性受损。这些研究表明，FAK可能是控制造血细胞沉积和谱系发育的信号通路中的关键中介。
Hematopoietic stem/progenitor cells (HSC/P) reside in the bone marrow in distinct anatomic locations (niches) to receive growth, survival and differentiation signals. HSC/P localization and migration between niches depend on cell-cell and cell-matrix interactions, which result from the cooperation of cytokines, chemokines and adhesion molecules. The CXCL12-CXCR4 pathway, in particular, is essential for myelopoiesis and B lymphopoiesis but the molecular mechanisms of CXCL12 action remain unclear. We previously noted a strong correlation between prolonged CXCL12-mediated focal adhesion kinase (FAK) phosphorylation and sustained pro-adhesive responses in progenitor B cells, but not in mature B cells. Although FAK has been well studied in adherent fibroblasts, its function in hematopoietic cells is not defined. We used two independent approaches to reduce FAK expression in (human and mouse) progenitor cells. RNA interference (RNAi)-mediated FAK silencing abolished CXCL12-induced responses in human pro-B leukemia, REH cells. FAK-deficient REH cells also demonstrated reduced CXCL12-induced activation of the GTPase Rap1, suggesting the importance of FAK in CXCL12-mediated integrin activation. Moreover, in FAK(flox/flox) hematopoietic precursor cells, Cre-mediated FAK deletion resulted in impaired CXCL12-induced chemotaxis. These studies suggest that FAK may function as a key intermediary in signaling pathways controlling hematopoietic cell lodgment and lineage development.