Negative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex.

Liang Weng,Naoya Asai,Yoshiharu Shimomura,Shinji Mii,Jian An,Masato Asai,Yi-Peng Han,Shushi Nagamori,Yasuyuki Kitaura,Maki Takagishi,Takashi Masuko,Atsushi Enomoto,Masahide Takahashi,Yoshikatsu Kanai,Kun-Liang Guan

doi:10.1371/journal.pbio.2005090

Abstract

Amino acid signaling mediated by the activation of mechanistic target of rapamycin complex 1 (mTORC1) is fundamental to cell growth and metabolism. However, how cells negatively regulate amino acid signaling remains largely unknown. Here, we show that interaction between 4F2 heavy chain (4F2hc), a subunit of multiple amino acid transporters, and the multifunctional hub protein girders of actin filaments (Girdin) down-regulates mTORC1 activity. 4F2hc interacts with Girdin in mitogen-activated protein kinase (MAPK)- and amino acid signaling–dependent manners to translocate to the lysosome. The resultant decrease in cell surface 4F2hc leads to lowered cytoplasmic glutamine (Gln) and leucine (Leu) content, which down-regulates amino acid signaling. Consistently, Girdin depletion augments amino acid-induced mTORC1 activation and inhibits amino acid deprivation–induced autophagy. These findings uncovered the mechanism underlying negative regulation of amino acid signaling, which may play a role in tightly regulated cell growth and metabolism.

Highlights

Cells respond to extracellular stimuli through multiple signaling pathways, which govern and coordinate various cellular activities
We revealed that an endocytosis-related protein called girders of actin filaments (Girdin) negatively regulates amino acid–induced mechanistic target of rapamycin complex 1 (mTORC1) activation via the formation of a complex with 4F2 heavy chain
Amino acids activate the mechanistic target of rapamycin complex 1, which is a signaling complex composed of a conserved serine-threonine kinase mechanistic target of rapamycin, Raptor, mammalian lethal with SEC13 protein 8, Deptor, and the proline-rich Akt substrate of 40 kDa (PRAS40) [5]. mTORC1 is essential for multiple biological processes, such as cell growth, anabolism, and autophagy [6]

Summary

Introduction

Cells respond to extracellular stimuli through multiple signaling pathways, which govern and coordinate various cellular activities. Because of their vital roles, these signaling pathways need to be precisely controlled so that cells can respond appropriately to the external cues and maintain cell homeostasis [1]. Mechanisms by which amino acids function to control several cellular processes have attracted considerable attention [4]. Amino acids activate the mechanistic target of rapamycin complex 1 (mTORC1), which is a signaling complex composed of a conserved serine-threonine kinase mechanistic target of rapamycin (mTOR), Raptor, mammalian lethal with SEC13 protein 8 (mLST8), Deptor, and the proline-rich Akt substrate of 40 kDa (PRAS40) [5]. MTORC1 signaling is frequently deregulated in several diseases, including cancer and diabetes, which makes it an attractive target for drug discovery [7]

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Conclusion