The molecular mechanisms regulating oncogenic signalling by sphingosine kinase 1 phosphorylation and localisation

鞘氨醇激酶是一种产生脂质信号分子的酶，鞘氨醇磷酸参与调节多种重要的哺乳动物细胞功能。研究发现鞘氨醇激酶参与促进细胞的生长和存活。鞘氨醇激酶的失调参与了肿瘤的发生，如果能阻断其活性，就能减小肿瘤的大小。因此，这为癌症治疗干预提供了一个潜在的靶点。然而，细胞调节鞘氨醇激酶的方式尚不清楚。众所周知，鞘氨醇激酶的磷酸化会增加这种酶的活性，并导致其在质膜上的定位发生变化。我们发现这两个过程对鞘氨醇激酶的致瘤作用都是必不可少的，但对这些过程在细胞中是如何实现的知之甚少。本研究将探讨这一问题，并认为了解这些过程将有助于开发新的药物来阻断鞘氨醇激酶的致瘤作用。

Sphingosine kinase is an enzyme that produces the lipid signalling molecule, sphingosine phosphate that is involved in the regulation of a diverse array of important mammalian cellular functions. Studies have found that sphingosine kinase is involved in enhancing the growth and survival of cells. Disregulation of sphingosine kinase is involved in tumorigenesis, and if its activity can be blocked, tumor size can be reduced. Therefore, this provides a potential target for therapeutic intervention in cancer. However, the manner by which cells regulate sphingosine kinase is not well known. It is known that phosphorylation of sphingosine kinase increases the activity of this enzyme, and also causes a shift in its localisation the the plasma membrane. We have found that both of these processes are essential for the tumorigenic effects of sphingosine kinase, but very little is known about how these processes are achieved in the cell. This study will investigate this problem with the view that understanding these processes will assist in the development of new drugs to block the tumorigenic effects of sphingosine kinase.