Myosin 1-mediated Exocytosis of Glucose Transporter Storage Vesicles

该项目旨在更好地了解葡萄糖转运蛋白储存囊泡胞吐作用背后的肌球蛋白1依赖的机制。我们将研究Myo1c和Myo1b在葡萄糖转运蛋白4装载的小泡运输中的作用，以及脂肪细胞和心肌细胞中信号事件与小泡运输机制之间的联系。以肌动蛋白为基础的细胞质运动蛋白Myo1c的特征及其与脂肪细胞中伙伴蛋白的调节相互作用是我们工作计划的核心。我们提出了一种机制，通过PKA介导的Myo1c颈部区域的磷酸化以及随后IQ1处的钙调蛋白被14-3-3取代，导致激活的Myo1c二聚体的形成，促进与诸如Kinesin-1等磷酸蛋白的特异性相互作用。此外，IQ1上钙调蛋白被14-3-3取代预计会破坏Myo1c单体与192 kDa磷酸蛋白Rictor的钙敏感相互作用，Rictor是大蛋白激酶mTOR的结合伙伴。我们将研究Myo1b在肌细胞中的作用和相互作用伙伴，并将我们的研究扩展到肌球蛋白1依赖的过程在特定类型的癌细胞摄取葡萄糖中的作用。

The project aims at a better understanding of myosin 1-dependent mechanisms underlying the exocytosis of glucose transporter storage vesicles. We will examine the role of Myo1c and Myo1b in the trafficking of glucose transporter 4 loaded vesicles and links between signalling events and the vesicle-trafficking machinery in adipocytes and myocyte. The characterisation of the cytoplasmic, actin-based motor protein Myo1c and its regulated interaction with partner proteins in adipocytes are at the heart of our work program. We propose a mechanism by which PKA-mediated phosphorylation of the Myo1c neck region and the ensuing replacement of calmodulin at IQ1 by 14-3-3 leads to the formation of activated Myo1c dimers, promotes specific interactions with phosphoproteins such as kinesin-1. Additionally, replacement of calmodulin at IQ1 by 14-3-3 is predicted to disrupt the Ca2+-sensitive interactions of Myo1c monomers with the 192 kDa phosphoprotein Rictor, a binding partner of the large protein kinase mTOR. We will examine the role and interaction partners of Myo1b in myocytes and extend our studies to the role of myosin 1-dependent process in the uptake of glucose by specific types of cancer cells.