Characterization of an Alternative Splice Variant of LKB1

被引:33
作者
Denison, Fiona C. [1 ]
Hiscock, Natalie J. [2 ]
Carling, David [1 ]
Woods, Angela [1 ]
机构
[1] Ctr Clin Sci, MRC, Cellular Stress Grp, London W12 0NN, England
[2] Personalised Vital Platform, Unilever Discover, Sharnbrook MK44 1LQ, Beds, England
基金
英国医学研究理事会;
关键词
ACTIVATED PROTEIN-KINASE; JEGHERS CANCER SYNDROME; TUMOR-SUPPRESSOR; ENDOTHELIAL-CELLS; SKELETAL-MUSCLE; UPSTREAM KINASE; IN-VITRO; C-ZETA; PHOSPHORYLATION; COMPLEX;
D O I
10.1074/jbc.M806153200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
LKB1 is an upstream activating kinase for the AMP-activated protein kinase (AMPK) and at least 12 other AMPK-related kinases. LKB1 therefore acts as a master kinase regulating the activity of a wide range of downstream kinases, which themselves have diverse physiological roles. Here we identify a second form of LKB1 generated by alternative splicing of the LKB1 gene. The two LKB1 proteins have different C-terminal sequences generating a 50-kDa form (termed LKB1(L)) and a 48-kDa form (LKB1(S)). LKB1(L) is widely expressed in mouse tissues, whereas LKB1S has a restricted tissue distribution with predominant expression in the testis. LKB1(S), like LKB1(L), forms a complex with MO25 and STRAD, and phosphorylates and activates AMPK both in vitro and in intact cells. A phosphorylation site (serine 431 in mouse) and a farnesylation site (cysteine 433 in mouse) within LKB1(L) are not conserved in LKB1(S) raising the possibility that these sites might be involved in differential regulation and/or localization of the two forms of LKB1. However, we show that phosphorylation of serine 431 has no effect on LKB1(L) activity and that both LKB1(L) and LKB1(S) have similar patterns of subcellular localization. These results indicate that the physiological significance of the different forms of LKB1 is not related directly to differences in the C-terminal sequences but may be due to their differential patterns of tissue distribution.
引用
收藏
页码:67 / 76
页数:10
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