TBCK Influences Cell Proliferation, Cell Size and mTOR Signaling Pathway

Yueli Liu,Tianhua Zhou,Xiaoyi Yan,Robert Lafrenie

doi:10.1371/journal.pone.0071349

Yueli Liu, Tianhua Zhou + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0071349

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Journal: PloS one	Publication Date: Aug 19, 2013
Citations: 39	License type: CC BY 4.0

Affiliation: Zhejiang University

Abstract

Mammalian target of rapamycin (mTOR) is a central regulator for both cell proliferation and cell growth; however, little is known about the regulation of mTOR expression at the transcriptional level. Here, we provide evidences that a conserved human protein TBCK (TBC1 domain containing kinase) is involved in the regulation of mTOR signaling pathway. Depletion of TBCK significantly inhibits cell proliferation, reduces cell size, and disrupts the organization of actin, but not microtubule. Knockdown of TBCK induces a significant decrease in the protein levels of components of mTOR complex (mTORC), and suppresses the activity of mTOR signaling, but not MAPK or PDK1/Akt pathway. Further results show that TBCK influences the expression of mTORC components at the transcriptional level. Thus, these data suggest that TBCK may play an important role in cell proliferation, cell growth and actin organization possibly by modulating mTOR pathway.

Highlights

Cell proliferation and cell growth are distinct, but coupled processes that are essential for development of an organ and whole organism
MTORC1 has regulatory-associated protein of mammalian target of rapamycin (Raptor) and prolinerich Akt substrate of 40 kDa (PRAS40), whereas mTOR complex 2 (mTORC2) contains mammalian stress-activated map kinase-interacting protein 1, rapamycin-insensitive companion of Mammalian target of rapamycin (mTOR) (Rictor) and protein observed with Rictor 1 and 2 [6,10,11,12,13,14,15,16,17,18,19,20,21]. mTOR complex 1 (mTORC1) is rapamycin-sensitive and involved in cell proliferation, cell growth, metabolism, autophagy and so on [2,6]
BLAST searches for proteins homologous to human TBCK in other species revealed that putative orthologs of TBCK are highly conserved in C. elegans, D. melanogaster, D. rerio and M. musculus (Fig. 1A)

Summary

Introduction

Cell proliferation and cell growth (increased in cell size and cell mass) are distinct, but coupled processes that are essential for development of an organ and whole organism. MTOR interacts with several proteins to form two distinct complexes named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [6] Both complexes share mTOR, mammalian lethal with SEC13 protein 8/G-protein bsubunit like protein (mLST8/GbL), DEP domain containing mTOR-interacting protein (DEPTOR), and the Tit1/Tel complex [6,7,8,9]. MTORC1 has regulatory-associated protein of mammalian target of rapamycin (Raptor) and prolinerich Akt substrate of 40 kDa (PRAS40), whereas mTORC2 contains mammalian stress-activated map kinase-interacting protein 1 (mSin1), rapamycin-insensitive companion of mTOR (Rictor) and protein observed with Rictor 1 and 2 (protor1/2) [6,10,11,12,13,14,15,16,17,18,19,20,21]. MTORC2 is resistant to acute rapamycin treatment and participates in AKT (Ser473) pathway and actin cytoskeleton organization [16,17]

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