2011
DOI: 10.1074/jbc.m110.209114
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Rho-associated Kinase Connects a Cell Cycle-controlling Anchorage Signal to the Mammalian Target of Rapamycin Pathway

Abstract: When deprived of anchorage to the extracellular matrix, fibroblasts arrest in G 1 phase at least in part due to inactivation of G 1 cyclin-dependent kinases. Despite great effort, how anchorage signals control the G 1 -S transition of fibroblasts remains highly elusive. We recently found that the mammalian target of rapamycin (mTOR) cascade might convey an anchorage signal that regulates S phase entry. Here, we show that Rhoassociated kinase connects this signal to the TSC1/TSC2-RHEB-mTOR pathway. Expression o… Show more

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Cited by 23 publications
(26 citation statements)
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References 54 publications
(26 reference statements)
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“…Cell Construction-Rat embryonic fibroblasts (REFs) constitutively expressing human CDK6, mouse cyclin D3, rat Cdc6, C-terminal-truncated constitutively active human ROCK1 and/or constitutively active human Rheb from the cytomegalovirus promoter were constructed as described (14,17). The drugs used for selection were G418, hygromycin, puromycin, blasticidin, and zeocin.…”
Section: Methodsmentioning
confidence: 99%
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“…Cell Construction-Rat embryonic fibroblasts (REFs) constitutively expressing human CDK6, mouse cyclin D3, rat Cdc6, C-terminal-truncated constitutively active human ROCK1 and/or constitutively active human Rheb from the cytomegalovirus promoter were constructed as described (14,17). The drugs used for selection were G418, hygromycin, puromycin, blasticidin, and zeocin.…”
Section: Methodsmentioning
confidence: 99%
“…Forced activation of mTORC1, however, restores only Cdk4/Cdk6 activity despite marked up-regulation of both cyclin A and D-type cyclins and additional enforced Cdc6 expression. By contrast, expression of both a constitutively active ROCK and Cdc6 stimulates not only Cdk4/Cdk6 but also Cdk2 (17). Although ROCK may participate therein, how anchorage signals regulate Cdk2 activity is unknown.…”
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confidence: 96%
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“…To confirm PIM1-mediated C-terminal phosphorylation of p27 under anchorage deprivation in vivo and the functional distinction between PIM1 and ROCK1, we constructed by retrovirus-mediated gene transfer and analyzed REF- by withdrawal of doxycycline were constructed as before (15,16), induced or uninduced for enforced Cdc6 expression, and analyzed for Cdk2 activity and the levels of Rb Ser-780 phosphorylation and S6K1 Thr-389 phosphorylation, hallmarks of Cdk4/Cdk6 activity and mTORC1 activity, respectively. In this cell, induced Cdc6 protein was far more unstable than in mTORC1-activated cells perhaps because of inactivation of Cdk4/Cdk6 and consequent failed induction of Emi1 the G 1 phase inhibitor of the APC/C CDH1 ubiquitin ligase that degrades Cdc6 (17).…”
Section: Combined Overexpression Of Pim1 and Cdc6 Transiently Activatmentioning
confidence: 99%
“…In addition to these regulations, it was recently discovered that C-terminal Thr-197 phosphorylation of p27 is required for the activation of the p27-bound Cdk2 by Cdc6 the AAAϩ ATPase in an entirely new mechanism (15). Furthermore, this C-terminal phosphorylation was found to be exerted not only by PIM kinases but also by ROCK1 kinase that mediates an anchorage signal to promote actin fiber assembly as well as activate mTORC1 signaling (16,17). Thus, an additional biological role of C-terminal Thr-197 phosphorylation was discovered.…”
mentioning
confidence: 99%