Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Cell Metab. 2010 Feb 3;11(2):113-24. doi: 10.1016/j.cmet.2009.12.010.
Fyn null mice display reduced adiposity associated with increased fatty acid oxidation, energy expenditure, and activation of the AMP-dependent protein kinase (AMPK) in skeletal muscle and adipose tissue. The acute pharmacological inhibition of Fyn kinase activity with SU6656 in wild-type mice reproduces these metabolic effects and induced a specific reduction in fat mass with no change in lean mass. LKB1, the main upstream AMPK kinase (AMPKK) in peripheral tissues, was redistributed from the nucleus into the cytoplasm of cells treated with SU6656 and in cells expressing a kinase-deficient, but not a constitutively kinase-active, Fyn mutant. Moreover, Fyn kinase directly phosphorylated LKB1 on tyrosine 261 and 365 residues, and mutations of these sites resulted in LKB1 export into the cytoplasm and increased AMPK phosphorylation. These data demonstrate a crosstalk between Fyn tyrosine kinase and the AMPK energy-sensing pathway, through Fyn-dependent regulation of the AMPK upstream activator LKB1.
Fyn 缺失小鼠表现出脂肪量减少，伴随着脂肪酸氧化、能量消耗和骨骼肌及脂肪组织中 AMP 依赖的蛋白激酶（AMPK）的激活增加。在野生型小鼠中，使用 SU6656 进行 Fyn 激酶活性的急性药理学抑制可重现这些代谢效应，并特异性减少脂肪量而不改变瘦体量。LKB1 是外周组织中 AMPK 的主要上游激酶（AMPKK），在用 SU6656 处理的细胞和表达激酶缺陷但不是组成型激酶活性的 Fyn 突变体的细胞中，从细胞核重新分布到细胞质中。此外，Fyn 激酶可直接在酪氨酸残基 261 和 365 上磷酸化 LKB1，并且这些位点的突变导致 LKB1 输出到细胞质中并增加 AMPK 的磷酸化。这些数据表明，Fyn 酪氨酸激酶和 AMPK 能量感应途径之间存在串扰，通过 Fyn 依赖性调节 AMPK 的上游激活剂 LKB1。
