Grossmann Katja S, Wende Hagen, Paul Florian E, Cheret Cyril, Garratt Alistair N, Zurborg Sandra, Feinberg Konstantin, Besser Daniel, Schulz Herbert, Peles Elior, Selbach Matthias, Birchmeier Walter, Birchmeier Carmen
Neuroscience Department, Department of Cancer Research, Department of Cardiovascular Research, Max-Delbrück-Centrum for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin, Germany.
Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16704-9. doi: 10.1073/pnas.0904336106. Epub 2009 Sep 11.
The nonreceptor tyrosine phosphatase Shp2 (PTPN11) has been implicated in tyrosine kinase, cytokine, and integrin receptor signaling. We show here that conditional mutation of Shp2 in neural crest cells and in myelinating Schwann cells resulted in deficits in glial development that are remarkably similar to those observed in mice mutant for Neuregulin-1 (Nrg1) or the Nrg1 receptors, ErbB2 and ErbB3. In cultured Shp2 mutant Schwann cells, Nrg1-evoked cellular responses like proliferation and migration were virtually abolished, and Nrg1-dependent intracellular signaling was altered. Pharmacological inhibition of Src family kinases mimicked all cellular and biochemical effects of the Shp2 mutation, implicating Src as a primary Shp2 target during Nrg1 signaling. Together, our genetic and biochemical analyses demonstrate that Shp2 is an essential component in the transduction of Nrg1/ErbB signals.
非受体酪氨酸磷酸酶Shp2（PTPN11）参与了酪氨酸激酶、细胞因子和整合素受体信号传导。我们在此表明，神经嵴细胞和髓鞘形成雪旺细胞中Shp2的条件性突变导致胶质细胞发育缺陷，这与在Neuregulin-1（Nrg1）或Nrg1受体ErbB2和ErbB3突变的小鼠中观察到的缺陷非常相似。在培养的Shp2突变雪旺细胞中，Nrg1引发的细胞反应如增殖和迁移几乎被消除，并且Nrg1依赖的细胞内信号传导发生改变。Src家族激酶的药理学抑制模拟了Shp2突变的所有细胞和生化效应，表明Src是Nrg1信号传导过程中Shp2的主要靶点。总之，我们的遗传和生化分析表明，Shp2是Nrg1/ErbB信号转导中的一个重要组成部分。
