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CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation.

Signaling through the second messengers calcium and diacylglycerol (DAG) is a critical element in many biological systems. Integration of calcium and DAG signals has been suggested to occur primarily through protein kinase C family members, which bind both calcium and DAG. However, an alternative pathway may involve members of the CalDAG-GEF/RasGRP protein family, which have structural features (calcium-binding EF hands and DAG-binding C1 domains) that suggest they can function in calcium and DAG signal integration. To gain insight into the signaling systems that may be regulated by CalDAG-GEF/RasGRP family members, we have focused on CalDAG-GEFI, which is expressed preferentially in the brain and blood. Through genetic ablation in the mouse, we have found that CalDAG-GEFI is crucial for signal integration in platelets. Mouse platelets that lack CalDAG-GEFI are severely compromised in integrin-dependent aggregation as a consequence of their inability to signal through CalDAG-GEFI to its target, the small GTPase Rap1. These results suggest that analogous signaling defects are likely to occur in the central nervous system when CalDAG-GEFI is absent or compromised in function.

Pubmed ID: 15334074


  • Crittenden JR
  • Bergmeier W
  • Zhang Y
  • Piffath CL
  • Liang Y
  • Wagner DD
  • Housman DE
  • Graybiel AM


Nature medicine

Publication Data

September 1, 2004

Associated Grants

  • Agency: NIMH NIH HHS, Id: F32-MH065815
  • Agency: NHLBI NIH HHS, Id: HL66105
  • Agency: NHLBI NIH HHS, Id: P01 HL056949
  • Agency: NHLBI NIH HHS, Id: P01-HL56949
  • Agency: NICHD NIH HHS, Id: R01-HD28341

Mesh Terms

  • Animals
  • Blood Cell Count
  • Calcium
  • DNA Primers
  • DNA-Binding Proteins
  • Diglycerides
  • Flow Cytometry
  • Genotype
  • Guanine Nucleotide Exchange Factors
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Platelet Aggregation
  • Second Messenger Systems
  • Signal Transduction
  • Thrombosis
  • rap1 GTP-Binding Proteins