SIK3 的功能研究

Abstract

SIK3隸屬於AMPK家族一員的SIK次家族，為一被廣泛表現的蛋白激酶。已有報告指出，SIK3在果蠅與人類之中肩負著調控能量平衡以及細胞週期的功能。SIK3由磷酸域，UBA域，PKA催化位址以及富含麩醯胺的C端所組成。SIK3的蛋白激酶活性咸信是由LKB1以及GSK-3β所調控。這兩個上游的蛋白激酶將SIK3位於催化環上的蘇氨酸163給磷酸化，藉此提升SIK3作為激酶的活性。SIK3與SIK1和SIK2在催化域的序列上具有高度的同源性。如同失去活性的SIK2 K49M的突變，SIK3的K41M以及K37M的突變同為失去激酶活性的型態。降低內生性的SIK3將會導致蛋白質組合錯誤反應的上升以及增加內質網的負擔同時損毀內質網蛋白質降解路徑。外源性過表現SIK3和SIK3將加速變性內質網蛋白質降解路徑的進行，反之，降低內生性的SIK2和SIK3將導致此一路經遭到抑制。在這個研究中，我試著去探討SIK2 SIK3以及UBQLN在變性內質網蛋白質降解路徑中的角色。

Salt-inducible kinase 3 (SIK3) is a ubiquitously expressed kinase which belongs to member of AMPK family and SIK sub-family. SIK3 has been reported to regulate energy homeostasis and cell cycle in Drosophila and Human. SIK3 is composed of kinase domain, UBA domain, PKA site and Q-rich C-terminal region. The kinase activity of SIK3 is thought to be regulated by LKB1 and GSK-3β. These two kinases could phosphorylate Thr163 in the activation loop to enhance SIK3 kinase activity. SIK3 shares extensive sequence homology with SIK1 and SIK2 in the ATP-binding pocket and catalytic domain. Similar to SIK2 kinase dead mutant SIK2-K49M, SIK3-K37M or K41M mutant is also kinase dead. Knockdown of SIK3 leads to activation of unfolded protein response (UPR) and impaired ER-associated degradation (ERAD). Overexpression of SIK2 or SIK3 can facilitate ERAD process. In contrast, knockdown of SIK2 or SIK3 lead to inhibition of ERAD. In this study, I investigate the potential roles of SIK2, SIK3 and UBQLN1/2 in regulating ERAD.