The ROCO Kinase QkgA Is Necessary for Proliferation Inhibition by Autocrine Signals in Dictyostelium discoideum

Phillips, Jonathan E.; Gomer, Richard H.

doi:10.1128/ec.00121-10

Cited by 24 publications

(64 citation statements)

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“…We previously found that colonies of aprA − and cfaD − cells expand less rapidly than wildtype cells on a lawn of bacteria, although these mutants show no difference in random cell motility at low cell density compared with wild type (31). To test whether wild-type cells show a directed movement away from areas of high cell density, we established small colonies of wild-type cells in growth media and measured the displacement of individual cells at the colony edges by video microscopy.…”

Section: Resultsmentioning

confidence: 95%

“…The G protein Gα8, the kinase QkgA, and the putative transcription factor BzpN are necessary for the proliferation-inhibiting activity of AprA (29,31,32), implicating these proteins in AprA signaling. Additionally, the secreted protein CfaD is necessary for AprA activity (30).…”

Section: Fig 2 Rapra But Not Rcfad Repels Cells (A)mentioning

confidence: 99%

“…AprA shows saturable binding to cells (27) and, although no receptor has been identified, AprA requires the heterotrimeric G protein complex components Gα8 and Gβ to inhibit proliferation, to induce high-affinity GTP binding to membranes (29), and for the GTP analog GTPγS to inhibit the binding of recombinant AprA (rAprA) to cell membranes (29). Inhibition of proliferation by AprA also requires the secreted protein CfaD (30), the ROCO kinase QkgA (31), and the putative transcription factor BzpN (32), implicating these proteins in signal transduction by AprA. Interestingly, although aprA − cells are able to chemotax toward cAMP, as evidenced by the ability of the cells to aggregate, and aprA − cells show random motility like that of wild-type cells, colonies of aprA − cells show a reduced rate of expansion compared with wild type (31).…”

mentioning

confidence: 99%

“…Inhibition of proliferation by AprA also requires the secreted protein CfaD (30), the ROCO kinase QkgA (31), and the putative transcription factor BzpN (32), implicating these proteins in signal transduction by AprA. Interestingly, although aprA − cells are able to chemotax toward cAMP, as evidenced by the ability of the cells to aggregate, and aprA − cells show random motility like that of wild-type cells, colonies of aprA − cells show a reduced rate of expansion compared with wild type (31). In this report, we provide evidence indicating that AprA functions as an autocrine chemorepellant for vegetative Dictyostelium cells.…”

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confidence: 99%

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A secreted protein is an endogenous chemorepellant in Dictyostelium discoideum

Phillips

Gomer

2012

Proc. Natl. Acad. Sci. U.S.A.

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104

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Chemorepellants may play multiple roles in physiological and pathological processes. However, few endogenous chemorepellants have been identified, and how they function is unclear. We found that the autocrine signal AprA, which is produced by growing Dictyostelium discoideum cells and inhibits their proliferation, also functions as a chemorepellant. Wild-type cells at the edge of a colony show directed movement outward from the colony, whereas cells lacking AprA do not. Cells show directed movement away from a source of recombinant AprA and dialyzed conditioned media from wild-type cells, but not dialyzed conditioned media from aprA − cells. The secreted protein CfaD, the G protein Gα8, and the kinase QkgA are necessary for the chemorepellant activity of AprA as well as its proliferation-inhibiting activity, whereas the putative transcription factor BzpN is dispensable for the chemorepellant activity of AprA but necessary for inhibition of proliferation. Phospholipase C and PI3 kinases 1 and 2, which are necessary for the activity of at least one other chemorepellant in Dictyostelium , are not necessary for recombinant AprA chemorepellant activity. Starved cells are not repelled by recombinant AprA, suggesting that aggregation-phase cells are not sensitive to the chemorepellant effect. Cell tracking indicates that AprA affects the directional bias of cell movement, but not cell velocity or the persistence of cell movement. Together, our data indicate that the endogenous signal AprA acts as an autocrine chemorepellant for Dictyostelium cells.

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Section: Resultsmentioning

confidence: 95%

Section: Fig 2 Rapra But Not Rcfad Repels Cells (A)mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A secreted protein is an endogenous chemorepellant in Dictyostelium discoideum

Phillips

Gomer

2012

Proc. Natl. Acad. Sci. U.S.A.

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104

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“…CfaD and AprA are secreted during growth and are part of an extracellular 150-kDa complex that represses proliferation but does not affect cell growth (1,6). A receptor for AprA has been characterized (8), and the signaling pathway downstream of the chalone receptor involves G proteins (2) and a ROCO family kinase (26). While there is some understanding of the mechanism of action of CfaD and AprA in inhibiting proliferation, nothing is known about the control of their production.…”

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confidence: 99%

eIF2α Kinases Control Chalone Production in Dictyostelium discoideum

et al. 2011

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Growing Dictyostelium cells secrete CfaD and AprA, two proteins that have been characterized as chalones. They exist within a high-molecular-weight complex that reversibly inhibits cell proliferation, but not growth, via cell surface receptors and a signaling pathway that includes G proteins. How the production of these two proteins is regulated is unknown. Dictyostelium cells possess three GCN2-type eukaryotic initiation factor 2 ␣ subunit (eIF2␣) kinases, proteins that phosphorylate the translational initiation factor eIF2␣ and possess a tRNA binding domain involved in their regulation. The Dictyostelium kinases have been shown to function during development in regulating several processes. We show here that expression of an unregulated, activated kinase domain greatly inhibits cell proliferation. The inhibitory effect on proliferation is not due to a general inhibition of translation. Instead, it is due to enhanced production of a secreted factor(s). Indeed, extracellular CfaD and AprA proteins, but not their mRNAs, are overproduced in cells expressing the activated kinase domain. The inhibition of proliferation is not seen when the activated kinase domain is expressed in cells lacking CfaD or AprA or in cells that contain a nonphosphorylatable eIF2␣. We conclude that production of the chalones CfaD and AprA is translationally regulated by eIF2␣ phosphorylation. Both proteins are upregulated at the culmination of development, and this enhanced production is lacking in a strain that possesses a nonphosphorylatable eIF2␣.

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Functional similarities between the dictyostelium protein AprA and the human protein dipeptidyl‐peptidase IV

et al. 2017

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Autocrine proliferation repressor protein A (AprA) is a protein secreted by Dictyostelium discoideum cells. Although there is very little sequence similarity between AprA and any human protein, AprA has a predicted structural similarity to the human protein dipeptidyl peptidase IV (DPPIV). AprA is a chemorepellent for Dictyostelium cells, and DPPIV is a chemorepellent for neutrophils. This led us to investigate if AprA and DPPIV have additional functional similarities. We find that like AprA, DPPIV is a chemorepellent for, and inhibits the proliferation of, D. discoideum cells, and that AprA binds some DPPIV binding partners such as fibronectin. Conversely, rAprA has DPPIV-like protease activity. These results indicate a functional similarity between two eukaryotic chemorepellent proteins with very little sequence similarity, and emphasize the usefulness of using a predicted protein structure to search a protein structure database, in addition to searching for proteins with similar sequences.

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The ROCO Kinase QkgA Is Necessary for Proliferation Inhibition by Autocrine Signals in Dictyostelium discoideum

Abstract: AprA and CfaD are secreted proteins that function as autocrine signals to inhibit cell proliferation in

Cited by 24 publications

References 41 publications

A secreted protein is an endogenous chemorepellant in Dictyostelium discoideum

A secreted protein is an endogenous chemorepellant in Dictyostelium discoideum

eIF2α Kinases Control Chalone Production in Dictyostelium discoideum

Functional similarities between the dictyostelium protein AprA and the human protein dipeptidyl‐peptidase IV

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