PMID- 15572660
OWN - NLM
STAT- MEDLINE
DCOM- 20041230
LR  - 20201209
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 24
IP  - 24
DP  - 2004 Dec
TI  - A vascular gene trap screen defines RasGRP3 as an angiogenesis-regulated gene 
      required for the endothelial response to phorbol esters.
PG  - 10515-28
AB  - We identified Ras guanine-releasing protein 3 (RasGRP3) as a guanine exchange 
      factor expressed in blood vessels via an embryonic stem (ES) cell-based gene trap 
      screen to identify novel vascular genes. RasGRP3 is expressed in embryonic blood 
      vessels, down-regulated in mature adult vessels, and reexpressed in newly formed 
      vessels during pregnancy and tumorigenesis. This expression pattern is consistent 
      with an angiogenic function for RasGRP3. Although a loss-of-function mutation in 
      RasGRP3 did not affect viability, RasGRP3 was up-regulated in response to 
      vascular endothelial growth factor (VEGF) stimulation of human umbilical vein 
      endothelial cells, placing RasGRP3 regulation downstream of VEGF signaling. 
      Phorbol esters mimic the second messenger diacylglycerol (DAG) in activating both 
      protein kinase C (PKC) and non-PKC phorbol ester receptors such as RasGRP3. ES 
      cell-derived wild-type blood vessels exposed to phorbol myristate acetate (PMA) 
      underwent extensive aberrant morphogenesis that resulted in the formation of 
      large endothelial sheets rather than properly branched vessels. This response to 
      PMA was completely dependent on the presence of RasGRP3, as mutant vessels were 
      refractory to the treatment. Taken together, these findings show that endothelial 
      RasGRP3 is up-regulated in response to VEGF stimulation and that RasGRP3 
      functions as an endothelial cell phorbol ester receptor in a pathway whose 
      stimulation perturbs normal angiogenesis. This suggests that RasGRP3 activity may 
      exacerbate vascular complications in diseases characterized by excess DAG, such 
      as diabetes.
FAU - Roberts, David M
AU  - Roberts DM
AD  - Curriculum in Genetics and Molecular Biology, Department of Biology, CB#3280, 
      University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
FAU - Anderson, Amanda L
AU  - Anderson AL
FAU - Hidaka, Michihiro
AU  - Hidaka M
FAU - Swetenburg, Raymond L
AU  - Swetenburg RL
FAU - Patterson, Cam
AU  - Patterson C
FAU - Stanford, William L
AU  - Stanford WL
FAU - Bautch, Victoria L
AU  - Bautch VL
LA  - eng
GR  - R01 HL043174/HL/NHLBI NIH HHS/United States
GR  - R21 HL071993/HL/NHLBI NIH HHS/United States
GR  - HL 43174/HL/NHLBI NIH HHS/United States
GR  - HL 71993/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 0 (Phorbol Esters)
RN  - 0 (RASGRP3 protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (ras Guanine Nucleotide Exchange Factors)
RN  - EC 2.7.1.107 (Diacylglycerol Kinase)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cell Line
MH  - Chromosome Mapping
MH  - Diacylglycerol Kinase/metabolism
MH  - Endothelium, Vascular/drug effects/*metabolism
MH  - Female
MH  - *Gene Expression Regulation, Developmental
MH  - Genetic Vectors
MH  - Guanine Nucleotide Exchange Factors/chemistry/genetics/*metabolism
MH  - Humans
MH  - Mice
MH  - Models, Biological
MH  - Molecular Sequence Data
MH  - Neovascularization, Physiologic/*drug effects
MH  - Phorbol Esters/metabolism/*pharmacology
MH  - Pregnancy
MH  - Protein Kinase C/metabolism
MH  - Protein Structure, Tertiary
MH  - Sequence Homology, Amino Acid
MH  - Signal Transduction
MH  - Stem Cells/cytology/drug effects
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - Umbilical Veins/cytology
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A/metabolism
MH  - ras Guanine Nucleotide Exchange Factors
PMC - PMC533983
EDAT- 2004/12/02 09:00
MHDA- 2004/12/31 09:00
PMCR- 2004/12/01
CRDT- 2004/12/02 09:00
PHST- 2004/12/02 09:00 [pubmed]
PHST- 2004/12/31 09:00 [medline]
PHST- 2004/12/02 09:00 [entrez]
PHST- 2004/12/01 00:00 [pmc-release]
AID - 24/24/10515 [pii]
AID - 1229-04 [pii]
AID - 10.1128/MCB.24.24.10515-10528.2004 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2004 Dec;24(24):10515-28. doi: 10.1128/MCB.24.24.10515-10528.2004.