PMID- 15894621
OWN - NLM
STAT- MEDLINE
DCOM- 20050804
LR  - 20240314
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 102
IP  - 21
DP  - 2005 May 24
TI  - Diacylglycerol kinase iota regulates Ras guanyl-releasing protein 3 and inhibits 
      Rap1 signaling.
PG  - 7595-600
AB  - To study the physiological function of diacylglycerol (DAG) kinase iota 
      (DGKiota), which converts DAG to phosphatidic acid, we deleted this gene in mice. 
      In contrast to previous studies showing that DGK isoforms decrease Ras activity, 
      signaling downstream of Ras in embryonic fibroblasts was significantly reduced in 
      cells lacking DGKiota. DGKs regulate Ras signaling by attenuating the function of 
      the DAG-dependent Ras guanyl nucleotide-releasing proteins (RasGRPs). We tested 
      whether DGKiota inhibited the four known RasGRPs and found that it inhibited only 
      RasGRP3. In addition to activating Ras, RasGRP3 also activates Rap1, which in 
      some cases can antagonize the function of Ras. We demonstrate that DGKiota bound 
      to RasGRP3 and inhibited its activation of Rap1 by metabolizing DAG. This 
      inhibition consequently affected Ras signaling. We tested the physiological 
      consequence of deleting DGKiota by crossing wild-type or DGKiota-deficient mice 
      with mice carrying a v-Ha-Ras transgene, and then we assessed tumor formation. We 
      observed significantly fewer tumors in DGKiota-deficient mice. Because Rap1 can 
      antagonize the function of Ras, our data are consistent with a model in which 
      DGKiota regulates RasGRP3 with a predominant effect on Rap1 activity. 
      Additionally, we found that DGKzeta, which is structurally similar to DGKiota, 
      inhibited RasGRPs 1, 3, and 4 and predominantly affected Ras signaling. Thus, 
      type IV DGKs regulate RasGRPs, but the downstream effects differ depending on the 
      DGK.
FAU - Regier, Debra S
AU  - Regier DS
AD  - The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
FAU - Higbee, Jared
AU  - Higbee J
FAU - Lund, Katrina M
AU  - Lund KM
FAU - Sakane, Fumio
AU  - Sakane F
FAU - Prescott, Stephen M
AU  - Prescott SM
FAU - Topham, Matthew K
AU  - Topham MK
LA  - eng
GR  - F32 CA093048/CA/NCI NIH HHS/United States
GR  - R01 CA095463/CA/NCI NIH HHS/United States
GR  - 1F32CA93048/CA/NCI NIH HHS/United States
GR  - CA95463/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20050513
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (DNA Primers)
RN  - 0 (Diglycerides)
RN  - 0 (ras Guanine Nucleotide Exchange Factors)
RN  - EC 2.7.1.107 (Diacylglycerol Kinase)
RN  - EC 3.6.5.2 (rap1 GTP-Binding Proteins)
SB  - IM
MH  - Animals
MH  - Blotting, Southern
MH  - Blotting, Western
MH  - Cell Line
MH  - DNA Primers
MH  - Diacylglycerol Kinase/genetics/*metabolism
MH  - Diglycerides/metabolism
MH  - Enzyme Activation/physiology
MH  - Immunoprecipitation
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Mutagenesis, Site-Directed
MH  - Neoplasms, Experimental/*metabolism
MH  - Plasmids/genetics
MH  - Signal Transduction/*physiology
MH  - Transfection
MH  - rap1 GTP-Binding Proteins/*metabolism
MH  - ras Guanine Nucleotide Exchange Factors/*metabolism
PMC - PMC1140424
EDAT- 2005/05/17 09:00
MHDA- 2005/08/05 09:00
PMCR- 2005/11/24
CRDT- 2005/05/17 09:00
PHST- 2005/05/17 09:00 [pubmed]
PHST- 2005/08/05 09:00 [medline]
PHST- 2005/05/17 09:00 [entrez]
PHST- 2005/11/24 00:00 [pmc-release]
AID - 0500663102 [pii]
AID - 01027595 [pii]
AID - 10.1073/pnas.0500663102 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2005 May 24;102(21):7595-600. doi: 
      10.1073/pnas.0500663102. Epub 2005 May 13.