Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Leuk Res. 2011 Jul;35(7):961-4. doi: 10.1016/j.leukres.2011.04.003. Epub 2011 May 8.
Activating PTPN11 mutants promote hematopoietic progenitor hyperactivation of Erk and hypersensitivity to GM-CSF. We hypothesized that Kinase Suppressor of Ras 1 (KSR1) contributes to activating PTPN11-induced GM-CSF hypersensitivity. Bone marrow progenitors from WT and KSR1-/- mice expressing WT Shp2, Shp2E76K, or Shp2D61Y were evaluated functionally and biochemically. KSR1 activation and interaction with phospho-Erk was enhanced in Shp2D61Y- and ShpE76K-expressing cells. Genetic disruption of KSR1 partially normalized Shp2E76K-induced GM-CSF hypersensitivity, but failed to correct Shp2D61Y-induced GM-CSF hypersensitivity. Collectively, these studies suggest that cells expressing Shp2E76K have a greater dependence on KSR1 for GM-CSF hypersensitivity than cells expressing Shp2D61Y.
激活 PTPN11 突变体会促进 Erk 的造血祖细胞过度激活和对 GM-CSF 的过度敏感。我们假设 Ras 激酶抑制剂 1（KSR1）有助于激活 PTPN11 诱导的 GM-CSF 敏感性。从表达 WT Shp2、Shp2E76K 或 Shp2D61Y 的 WT 和 KSR1-/- 小鼠的骨髓祖细胞中进行功能和生化评估。Shp2D61Y 和 ShpE76K 表达细胞中 KSR1 的激活和与磷酸化-Erk 的相互作用增强。KSR1 的遗传破坏部分纠正了 Shp2E76K 诱导的 GM-CSF 敏感性，但未能纠正 Shp2D61Y 诱导的 GM-CSF 敏感性。总之，这些研究表明，表达 Shp2E76K 的细胞比表达 Shp2D61Y 的细胞对 GM-CSF 敏感性的依赖性更大。
