LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
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DOI：
10.1016/j.cub.2003.10.031
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发表时间：
2003-11-11
期刊：
影响因子：
9.2
通讯作者：
Carling, D
中科院分区：
文献类型：
--
作者：
Woods, A;Johnstone, SR;Carling, D
蛋白激酶LKB 1的失活突变导致人类显性遗传性癌症，称为Peutz-Jeghers综合征[1，2]。LKB 1的作用尚不清楚，并且在体内仅鉴定了LKB 1的一个靶点[3]。AMP活化蛋白激酶（AMPK）是蛋白激酶级联的下游组分，在能量稳态中起关键作用[4]。AMPK可能在保护身体免受代谢性疾病包括2型糖尿病[5，6]、肥胖[7]和心脏肥大[8]中起作用。我们先前报道了三种蛋白激酶（Elm 1，Pak 1和Tos 3 [9]）的鉴定，它们位于AMPK的酵母同源物Snf 1的上游。LKB 1与Elm 1、Pak 1和Tos 3具有序列相似性，我们证明LKB 1在催化亚基内的活化环苏氨酸（Thr 172）上磷酸化AMPK，并在体外活化AMPK [9]。在这里，我们研究了LKB 1是否对应于细胞提取物中存在的主要AMPKK活性。从大鼠肝脏中纯化的AMPKK对应于LKB 1，阻断细胞中的LKB 1活性可消除AMPK对不同刺激的激活。这些结果确定了两种蛋白激酶之间的联系，这两种蛋白激酶以前被认为是不相关的，不同的途径，与人类疾病有关。
Inactivating mutations in the protein kinase LKB1 lead to a dominantly inherited cancer in humans termed Peutz-Jeghers syndrome [1, 2]. The role of LKB1 is unclear, and only one target for LKB1 has been identified in vivo [3]. AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a pivotal role in energy homeostasis [4]. AMPK may have a role in protecting the body from metabolic diseases including type 2 diabetes [5, 6], obesity [7], and cardiac hypertrophy [8]. We previously reported the identification of three protein kinases (Elm1, Pak1, and Tos3 [9]) that lie upstream of Snf1, the yeast homologue of AMPK. LKB1 shares sequence similarity with Elm1, Pak1, and Tos3, and we demonstrated that LKB1 phosphorylates AMPK on the activation loop threonine (Thr172) within the catalytic subunit and activates AMPK in vitro [9]. Here, we have investigated whether LKB1 corresponds to the major AMPKK activity present in cell extracts. AMPKK purified from rat liver corresponds to LKB1, and blocking LKB1 activity in cells abolishes AMPK activation in response to different stimuli. These results identify a link between two protein kinases, previously thought to lie in unrelated, distinct pathways, that are associated with human diseases.