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.
Crittenden
Jill R
JR
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.
Bergmeier
Wolfgang
W
Zhang
Yanyu
Y
Piffath
Crystal L
CL
Liang
Yuqiong
Y
Wagner
Denisa D
DD
Housman
David E
DE
Graybiel
Ann M
AM
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
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