title: CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation.
abstract: 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.
authors.affiliation: Department of Brain and Cognitive Sciences, and McGovern Institute for Brain Research, Massachusetts Institute of Technology, 45 Carleton Street, E25-618, Cambridge, Massachusetts 02139, USA.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Crittenden
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bergmeier
authors.forename: Yanyu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Piffath
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Liang
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
authors.forename: David E
authors.initials: DE
authors.lastname: Housman
authors.forename: Ann M
authors.initials: AM
authors.lastname: Graybiel
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D002118:Calcium / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D005434:Flow Cytometry; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism* / Q000502:physiology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013927:Thrombosis / Q000378:metabolism / Q000503:physiopathology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D004075:Diglycerides; D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse; D020827:rap1 GTP-Binding Proteins; D002118:Calcium