A MAP4 kinase related to <i>Ste20</i> is a nutrient-sensitive regulator of mTOR signalling

Findlay, Greg M.; Yan, Lijun; Procter, Julia; Mieulet, Virginie; Lamb, Richard F.

doi:10.1042/bj20061881

Cited by 239 publications

(221 citation statements)

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“…Therefore, we evaluated the mRNA expression of the class 3 phosphatidylinositol kinase (hVps34) and the MAP kinase, MAP4K3, both of which have been associated with trafficking amino acids to mTOR (12,25,43). Interestingly, hVps34 mRNA at baseline was higher (2.4-fold) in the older compared with young subjects ( Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…mTOR is also positively regulated by amino acids, and in particular by leucine (2,3). To date, two molecules have been implicated in mediating signals from amino acids to mTOR: human vacuolar protein sorting-34 (hVps34) and mitogen-activated protein kinase kinase kinase kinase-3 (MAP4K3; 12,25,43). On the other hand, REDD1 and REDD2 have been identified as negative regulators of mTOR (17).…”

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confidence: 99%

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Expression of growth-related genes in young and older human skeletal muscle following an acute stimulation of protein synthesis

Drummond

Miyazaki

Dreyer

et al. 2009

Journal of Applied Physiology

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Expression of growth-related genes in young and older human skeletal muscle following an acute stimulation of protein synthesis

Drummond

Miyazaki

Dreyer

et al. 2009

Journal of Applied Physiology

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“…The presence of amino acids promotes Tor activity via Rag small guanosine triphosphatases (Rag GTPases) and MAP4K3. [27][28][29][30] In Drosophila, MAP4K3 and Rag GTPases are required for growth in response to amino acids and overexpression of Rag GTPases suppresses starvation-induced autophagic PCD in the fat body. 29,30 Furthermore, MAP4K3 has been shown to physically interact with Rag GTPases and amino acids regulate their association.…”

Section: Discussionmentioning

confidence: 99%

Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis

Pritchett

McCall

2012

Cell Death Differ

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Amino-acid starvation leads to an inhibition of cellular proliferation and the induction of programmed cell death (PCD) in the Drosophila ovary. Disruption of insulin signaling has been shown to inhibit the progression of oogenesis, but it is unclear whether this phenotype mimics starvation. Here, we investigate whether the insulin-mediated phosphoinositide kinase-3 pathway regulates PCD in mid oogenesis. We reasoned that under well-fed conditions, disruption of positive components of the insulin signaling pathway within the germline would mimic starvation and produce degenerating egg chambers. Surprisingly, mutants did not mimic starvation but instead produced many abnormal egg chambers in which the somatic follicle cells disappeared and the germline persisted. These abnormal egg chambers did not show an induction of caspases and lysosomes like that observed in wild-type (WT) degenerating egg chambers. Egg chambers from insulin signaling mutants were resistant to starvation-induced PCD, indicating that a complete block in insulin-signaling prevents the proper response to starvation. However, target of rapamycin (Tor) mutants did show a phenotype that mimicked WT starvation-induced PCD, indicating an insulin independent regulation of PCD via Tor signaling. These results suggest that inhibition of the insulin signaling pathway is not sufficient to regulate starvation-induced PCD in mid oogenesis. Furthermore, starvation-induced PCD is regulated by Tor signaling converging with the canonical insulin signaling pathway. The insulin-mediated class I phosphoinositide kinase-3 (PI3K) pathway is a highly conserved nutrient-sensing pathway in diverse organisms. In mammals, insulin signaling affects oocyte maturation and fertilization. 1,2 Mutations in the insulin signaling pathway in C. elegans can lengthen life span but reduce fertility. 3,4 Improper insulin signaling in Drosophila leads to reduced body size and female sterility. 5 Thus, insulin signaling is essential for reproduction in diverse organisms, but how this pathway regulates fertility is not fully understood.Proper nutrition during Drosophila oogenesis is critical for egg chamber production. 6-8 Depriving flies of yeast as a protein source leads to programmed cell death (PCD) at two stages: early oogenesis in the germarium and mid oogenesis during stages 7-9. 7 Egg chambers undergoing PCD during mid oogenesis are characterized by nuclear condensation and fragmentation of germline-derived nurse cells (NCs), engulfment by somatic follicle cells (FCs), and ultimately FC death. 5 During PCD in mid oogenesis, dying NCs show characteristics of both apoptotic and autophagic PCD. 5 The effector caspase Death caspase-1 (Dcp-1) is essential for germline PCD in mid oogenesis. dcp-1 mutants that have been starved display mid-stage egg chambers that have a persistence of uncondensed NC nuclei but an absence of FCs. 5 This phenotype indicates that the dcp-1 mutant germline is unable to die in response to starvation, although the FCs respond and undergo PCD. dcp-1 mutants ...

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“…Loss-and gain-of-function mutations of GNAS involved in the cyclic AMP-dependent pathway cause human diseases (Weinstein et al 2006). MAP4K3 is a component in the nutrient-responsive pathway affecting cell growth (Findlay et al 2007). Deregulated expression of various EPH receptors, including EPHB2, has been reported in diverse tumor types (Guo et al 2006;Jubb et al 2005).…”

Section: Gene Expression Profile By Inhibiting Krap Expression In Hctmentioning

confidence: 99%

Analysis of KRAP expression and localization, and genes regulated by KRAP in a human colon cancer cell line

et al. 2007

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We previously identified the human KRAP (Ki-ras-induced actin-interacting protein) gene from the cDNA library of human colon cancer HCT116 cells as one of the genes whose expression levels were up-regulated by activated Ki-ras. Although the KRAP gene is structurally conserved from fish to mammalian species, the expression pattern and function of KRAP still remain to be elucidated. Here, we have generated a specific polyclonal antibody for KRAP and characterized the histological expression of KRAP in mouse tissues. KRAP was ubiquitously expressed in mouse tissues, with high levels in pancreas, liver, and brown adipose tissues, and KRAP was co-localized with filamentous actin along the apical membranes in both pancreas and liver tissues. A subfractionation study revealed that KRAP is a cytoplasmic protein and that the majority is associated with the cytoskeleton. Furthermore, microarray gene expression profile by inhibiting KRAP expression in HCT116 cells showed that several receptors and signal molecules frequently deregulated in cancers were differentially expressed in the KRAP-knockdown cells. All of these results suggested that KRAP might be a cytoskeleton-associated protein involving the structural integrity and/or signal transductions in human cancers.

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A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling

Cited by 239 publications

References 20 publications

Expression of growth-related genes in young and older human skeletal muscle following an acute stimulation of protein synthesis

Expression of growth-related genes in young and older human skeletal muscle following an acute stimulation of protein synthesis

Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis

Analysis of KRAP expression and localization, and genes regulated by KRAP in a human colon cancer cell line

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