PP2A T61 ɛpsilon 是营养信号向 mTOR 传递途径中 MAP4K3 的抑制剂。
PP2A T61 epsilon is an inhibitor of MAP4K3 in nutrient signaling to mTOR.
机构信息
Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, AB T6G IZ2, Canada.
出版信息
Mol Cell. 2010 Mar 12;37(5):633-42. doi: 10.1016/j.molcel.2010.01.031.
The mammalian target of rapamycin (mTOR) pathway is activated by a variety of stimuli, including nutrients such as glucose and amino acids. The Ste20 family kinase MAP4K3 is regulated by amino acids and acts upstream of mTORC1. Here we investigate how MAP4K3 activity is regulated by amino acid sufficiency. We identify a transautophosphorylation site in the MAP4K3 kinase activation segment (Ser170) that is required for MAP4K3 activity and its activation of mTORC1 signaling. Following amino acid withdrawal, Ser170 is dephosphorylated via PP2A complexed to PR61 epsilon, a PP2A-targeting subunit. Inhibition of PR61 epsilon expression prevents MAP4K3 Ser170 dephosphorylation and impairs mTORC1 inhibition during amino acid withdrawal. We propose that during amino acid sufficiency Ser170-phosphorylated MAP4K3 activates mTORC1, but that upon amino acid restriction MAP4K3 preferentially interacts with PP2A(T61 epsilon), promoting dephosphorylation of Ser170, MAP4K3 inhibition, and, subsequently, inhibition of mTORC1 signaling.
哺乳动物雷帕霉素靶蛋白（mTOR）途径可被多种刺激激活，包括葡萄糖和氨基酸等营养物质。丝裂原活化蛋白激酶激酶 4（MAP4K3）家族激酶受氨基酸调控，并作用于 mTORC1 的上游。在此，我们研究了氨基酸充足时 MAP4K3 活性是如何受到调控的。我们在 MAP4K3 激酶激活片段（丝氨酸 170）中鉴定出一个自身磷酸化位点，该位点对于 MAP4K3 的活性及其对 mTORC1 信号的激活是必需的。在氨基酸耗尽后，Ser170 通过与 PR61 ɛ 结合的蛋白磷酸酶 2A（PP2A）复合物去磷酸化，PR61 ɛ 是一种 PP2A 靶向亚基。抑制 PR61 ɛ 的表达可防止 MAP4K3 Ser170 去磷酸化，并在氨基酸耗尽时损害 mTORC1 的抑制。我们提出，在氨基酸充足时，磷酸化的 Ser170 MAP4K3 激活 mTORC1，但在氨基酸限制时，MAP4K3 优先与蛋白磷酸酶 2A（T61 ɛ）相互作用，促进 Ser170 的去磷酸化、MAP4K3 的抑制，进而抑制 mTORC1 信号。
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