van Dijk T B, van Den Akker E, Amelsvoort M P, Mano H, Löwenberg B, von Lindern M
Institute of Hematology, Erasmus University Rotterdam, Rotterdam, The Netherlands.
Blood. 2000 Nov 15;96(10):3406-13.
Stem cell factor (SCF) has an important role in the proliferation, differentiation, survival, and migration of hematopoietic cells. SCF exerts its effects by binding to cKit, a receptor with intrinsic tyrosine kinase activity. Activation of phosphatidylinositol 3'-kinase (PI3-K) by cKit was previously shown to contribute to many SCF-induced cellular responses. Therefore, PI3-K-dependent signaling pathways activated by SCF were investigated. The PI3-K-dependent activation and phosphorylation of the tyrosine kinase Tec and the adapter molecule p62Dok-1 are reported. The study shows that Tec and Dok-1 form a stable complex with Lyn and 2 unidentified phosphoproteins of 56 and 140 kd. Both the Tec homology and the SH2 domain of Tec were identified as being required for the interaction with Dok-1, whereas 2 domains in Dok-1 appeared to mediate the association with Tec. In addition, Tec and Lyn were shown to phosphorylate Dok-1, whereas phosphorylated Dok-1 was demonstrated to bind to the SH2 domains of several signaling molecules activated by SCF, including Abl, CrkL, SHIP, and PLCgamma-1, but not those of Vav and Shc. These findings suggest that p62Dok-1 may function as an important scaffold molecule in cKit-mediated signaling.
干细胞因子（SCF）在造血细胞的增殖、分化、存活和迁移中发挥着重要作用。SCF通过与cKit结合发挥作用，cKit是一种具有内在酪氨酸激酶活性的受体。先前已表明，cKit激活磷脂酰肌醇3'-激酶（PI3-K）有助于许多SCF诱导的细胞反应。因此，对SCF激活的PI3-K依赖性信号通路进行了研究。报道了酪氨酸激酶Tec和衔接分子p62Dok-1的PI3-K依赖性激活和磷酸化。该研究表明，Tec和Dok-1与Lyn以及两种未鉴定的56和140kd磷蛋白形成稳定复合物。Tec的Tec同源结构域和SH2结构域均被确定为与Dok-1相互作用所必需，而Dok-1中的两个结构域似乎介导了与Tec的结合。此外，Tec和Lyn可使Dok-1磷酸化，而磷酸化的Dok-1可与SCF激活的几种信号分子的SH2结构域结合，包括Abl、CrkL、SHIP和PLCγ-1，但不与Vav和Shc的SH2结构域结合。这些发现表明，p62Dok-1可能在cKit介导的信号传导中作为重要的支架分子发挥作用。
