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.
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