Atypical PKC-ζ regulates SDF-1-mediated migration and development of human CD34+progenitor cells
Atypical PKC-ζ regulates SDF-1-mediated migration and development of human CD34+progenitor cells
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DOI：
10.1172/jci200521773
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发表时间：
2005-01-01
影响因子：
15.9
通讯作者：
Lapidot, T
中科院分区：
文献类型：
--
作者：
Petit, I;Goichberg, P;Lapidot, T
趋化因子基质细胞衍生因子-1 （SDF-1）及其受体CXCR4在骨髓中造血祖细胞的迁移、保留和发育中发挥重要作用。我们报道了不典型PKC-zeta直接参与未成熟人类CD34（+）富集细胞和白血病前b急性淋巴细胞白血病（ALL） G2细胞中的SDF-1信号传导。发现CD34（+）细胞对骨髓基质细胞的趋化性、细胞极化和粘附依赖于PKC-zeta。G2和U937细胞中PKC-zeta的过表达导致SDF-1的定向运动性增加。有趣的是，sdf -1诱导的前b ALL细胞系B1迁移受损与PKC-zeta表达降低相关。SDF-1触发PKC-zeta磷酸化、转运到质膜和激酶活性。此外，我们发现PI3K是PKC-zeta的激活剂，Pyk-2和ERK1/2是PKC-zeta的下游靶点。sdf -1诱导的增殖和MMP-9分泌也需要PKC-zeta激活。最后，我们发现，NOD/SCID小鼠骨髓中富含CD34（+）的人细胞的体内植入（而不是归巢）依赖于PKC-zeta，并且向小鼠注射抑制PKC-zeta假底物肽导致小鼠祖细胞的动员。我们的研究结果表明PKC-zeta在造血干细胞和祖细胞运动和发育的sdf -1依赖性调节中发挥核心作用。
The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, play a major role in migration, retention, and development of hematopoietic progenitors in the bone marrow. We report the direct involvement of atypical PKC-zeta in SDF-1 signaling in immature human CD34(+)-enriched cells and in leukemic pre-B acute lymphocytic leukemia (ALL) G2 cells. Chemotaxis, cell polarization, and adhesion of CD34(+) cells to bone marrow stromal cells were found to be PKC-zeta dependent. Overexpression of PKC-zeta in G2 and U937 cells led to increased directional motility to SDF-1. interestingly, impaired SDF-1-induced migration of the pre-B ALL cell line B1 correlated with reduced PKC-zeta expression. SDF-1 triggered PKC-zeta phosphorylation, translocation to the plasma membrane, and kinase activity. Furthermore we identified PI3K as an activator of PKC-zeta, and Pyk-2 and ERK1/2 as downstream targets of PKC-zeta. SDF-1-induced proliferation and MMP-9 secretion also required PKC-zeta activation. Finally, we showed that in vivo engraftment, but not homing, of human CD34(+)-enriched cells to the bone marrow of NOD/SCID mice was PKC-zeta dependent and that injection of mice with inhibitory PKC-zeta pseudosubstrate peptides resulted in mobilization of murine progenitors. Our results demonstrate a central role for PKC-zeta in SDF-1-dependent regulation of hematopoietic stem and progenitor cell motility and development.