O'Laughlin-Bunner B, Radosevic N, Taylor M L, DeBerry C, Metcalfe D D, Zhou M, Lowell C, Linnekin D
Basic Research Laboratory, Division of Basic Sciences, National Cancer Institute-Frederick, MD 21702, USA.
Blood. 2001 Jul 15;98(2):343-50. doi: 10.1182/blood.v98.2.343.
Stem cell factor (SCF) binds to c-Kit and is an important mediator of survival, growth, and function of hematopoietic progenitor cells and mast cells. Lyn and other Src family members are activated by SCF and associate with phosphorylated tyrosine residues in the c-Kit juxtamembrane region. However, studies using c-Kit mutants incapable of directly recruiting Src family members suggest this kinase family plays a minimal role in c-Kit stimulus-response coupling mechanisms. The objective of this study was to specifically target Lyn and subsequently address its role in SCF-mediated responses of primary hematopoietic progenitor cells and mast cells. To this end, a dominant-inhibitory Lyn mutant and Lyn-deficient mice were used. Transfection of normal murine mast cells with kinase-inactive Lyn impaired SCF-induced growth. Further, SCF-induced proliferation and chemotaxis of Lyn-deficient mast cells were less than for wild-type mast cells. SCF-induced growth of progenitor cells lacking Lyn was also reduced compared with that of wild-type progenitor cells. Impairment of SCF-mediated responses of Lyn-deficient mast cells and progenitor cells did not result from reductions in surface expression of c-Kit. These studies demonstrate that Lyn is required for normal SCF-mediated responses of primary progenitors and for a differentiated lineage.
干细胞因子（SCF）与c-Kit结合，是造血祖细胞和肥大细胞存活、生长及功能的重要介质。Lyn及其他Src家族成员被SCF激活，并与c-Kit近膜区域的磷酸化酪氨酸残基结合。然而，使用无法直接招募Src家族成员的c-Kit突变体进行的研究表明，该激酶家族在c-Kit刺激-反应偶联机制中作用极小。本研究的目的是特异性靶向Lyn，进而探讨其在SCF介导的原代造血祖细胞和肥大细胞反应中的作用。为此，使用了显性抑制性Lyn突变体和Lyn基因缺陷型小鼠。用激酶失活的Lyn转染正常小鼠肥大细胞会损害SCF诱导的生长。此外，Lyn基因缺陷型肥大细胞的SCF诱导增殖和趋化性低于野生型肥大细胞。与野生型祖细胞相比，缺乏Lyn的祖细胞的SCF诱导生长也有所降低。Lyn基因缺陷型肥大细胞和祖细胞的SCF介导反应受损并非由于c-Kit表面表达降低所致。这些研究表明，Lyn是原代祖细胞正常的SCF介导反应以及分化谱系所必需的。
