PROBING CELLULAR FUNCTIONS OF THE MINIBRAIN KINASE

迷你脑(MNB)基因被定位在人类21号染色体的唐氏综合症临界区。有证据表明，MNB基因剂量的增加，如21三体，与唐氏综合症的表型有关。MNB编码一种双特异性蛋白激酶，其细胞功能尚未确定。我们的初步结果表明，MnB激酶参与控制Dynamin-1的活性，而其酶活性又受Rabaptin-5和一种新的富含半胱氨酸的蛋白的调节。由于Dynamin-1和Rabaptin-5都是内吞机制的一部分，这也表明MNB激酶在调节胞内膜运输方面必须发挥重要作用。我们计划在本研究中追求以下具体目标：1.建立MNB激酶作为负责通过磷酸化来调节Dynamin-1生理活性的酶。2.探讨Rabaptin-5和富含半胱氨酸的蛋白对MNB激酶活性的调节机制。3.鉴定MNB激酶磷酸化的Dynamin-12的生化性质。4.研究MNB激酶过表达对细胞内膜转运的影响。

The Minibrain (Mnb) gene is mapped to the Down syndrome critical region of human chromosome 21. Evidence suggests that an elevated Mnb gene dosage, as in trisomy 21, contributes to Down syndrome phenotypes. The Mnb encodes a dual specificity protein kinase whose cellular function has yet to be determined. Our preliminary results suggest that MnB kinase is involved in controlling the activity of dynamin-1, while its enzymatic activity is in turn regulated by rabaptin-5 and a novel cysteine-rich protein. Since both dynamin-1 and rabaptin-5 are part of endocytosis machinery, it also suggests that the Mnb kinase must play an essential role in regulating endocytic membrane trafficking. We plan to pursue the following specific aims in this study: 1. To establish the Mnb kinase as the enzyme responsible for regulating dynamin-1 physiological activity through phosphorylation. 2. To determine the mechanisms of regulating the enzymatic activity of Mnb kinase by rabaptin-5 and the cysteine-rich protein. 3. To characterize the biochemical properties of dynamin-12 phosphorylated by Mnb kinase. 4. To study the effects of Mnb kinase over-expression on endocytic membrane trafficking.