Voss Katrin, Stahl Sonja, Schleider Elisa, Ullrich Sybille, Nickel Joachim, Mueller Thomas D, Felbor Ute
Department of Human Genetics, University of Würzburg, Biozentrum, Am Hubland, 97074 Würzburg, Germany.
Neurogenetics. 2007 Nov;8(4):249-56. doi: 10.1007/s10048-007-0098-9. Epub 2007 Jul 27.
Individuals carrying a mutation in one of the three cerebral cavernous malformation genes (CCM1/KRIT1, CCM2, CCM3) cannot be clinically distinguished, raising the possibility that they act within common molecular pathways. In this study, we demonstrate that CCM3 (PDCD10) coprecipitates and colocalizes with CCM2. We also show that CCM3 directly binds to serine/threonine kinase 25 (STK25, YSK1, SOK1) and the phosphatase domain of Fas-associated phosphatase-1 (FAP-1, PTPN13, PTP-Bas, PTP-BL). CCM3 is phosphorylated by STK25 but not by its other Yeast-Two hybrid interactor STK24, whereas the C-terminal catalytic domain of FAP-1 dephosphorylates CCM3. Finally, our experiments reveal that STK25 forms a protein complex with CCM2. Thus, our data link two proteins of unknown function, CCM3 and STK25, with CCM2, which is part of signaling pathways essential for vascular development and CCM pathogenesis.
携带三种脑海绵状血管畸形基因（CCM1/KRIT1、CCM2、CCM3）之一发生突变的个体在临床上无法区分，这增加了它们在共同分子途径中发挥作用的可能性。在本研究中，我们证明CCM3（PDCD10）与CCM2共沉淀并共定位。我们还表明，CCM3直接与丝氨酸/苏氨酸激酶25（STK25、YSK1、SOK1）和Fas相关磷酸酶-1（FAP-1、PTPN13、PTP-Bas、PTP-BL）的磷酸酶结构域结合。CCM3被STK25磷酸化，但不被其另一个酵母双杂交相互作用蛋白STK24磷酸化，而FAP-1的C末端催化结构域使CCM3去磷酸化。最后，我们的实验表明STK25与CCM2形成蛋白质复合物。因此，我们的数据将两个功能未知的蛋白质CCM3和STK25与CCM2联系起来，CCM2是血管发育和脑海绵状血管畸形发病机制所必需的信号通路的一部分。
