ABSTRACT
We describe an adult patient with an unruptured choroidal-type arteriovenous malformation (AVM) associated with progressive hydrocephalus. There was no evidence of mechanical obstruction of the ventricular system by the AVM nidus itself or a draining vein. However significant reflux into periventricular and transmedullary veins was demonstrated. Following partial targeted embolization of the AVM, no further reflux was observed, the patient's clinical deficits resolved, and the hydrocephalus improved. We suggest a hydrodynamic disorder as a potential pathomechanism of hydrocephalus in this adult patient with an unruptured AVM.
Subject(s)
Cerebrovascular Circulation/physiology , Choroid/abnormalities , Hydrocephalus/etiology , Intracranial Arteriovenous Malformations/complications , Cerebral Angiography , Cerebral Veins/diagnostic imaging , Cerebral Veins/physiopathology , Choroid/diagnostic imaging , Choroid/physiopathology , Embolization, Therapeutic , Humans , Hydrocephalus/pathology , Hydrocephalus/physiopathology , Intracranial Arteriovenous Malformations/physiopathology , Intracranial Arteriovenous Malformations/therapy , Magnetic Resonance Imaging , Male , Middle AgedABSTRACT
Stimulation of the T-cell receptor (TCR) alters a number of intracellular signaling pathways including one that involves protein tyrosine kinases, phospholipase C-gamma1 (PLC-gamma1), diacylglycerol (DAG), and calcium messengers. By a divergent pathway, TCR-stimulated protein tyrosine kinase activity is thought to result independently in recruitment of the Ras activator Sos to the plasma membrane, leading to Ras activation. Here we show that RasGRP, a Ras activator that contains calcium-binding EF hands and a DAG-binding domain, is expressed in T cells. A PLC-gamma1 inhibitor diminished activation of Ras following TCR stimulation. Membranes from TCR-stimulated Jurkat T cells exhibited increased RasGRP and increased Ras-guanyl nucleotide association activity that was inhibited by antibodies directed against RasGRP. Overexpression of RasGRP in T cells enhanced TCR-Ras-Erk signaling and augmented interleukin-2 secretion in response to calcium ionophore plus DAG analogues phorbol ester myristate or bryostatin-1. Thus, RasGRP links TCR and PLC-gamma1 to Ras-Erk signaling, a pathway amenable to pharmacologic manipulation.
Subject(s)
DNA-Binding Proteins/immunology , Guanine Nucleotide Exchange Factors , Receptors, Antigen, T-Cell/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology , ras Proteins/immunology , Animals , Cell Line , Lymphocyte Activation/immunology , MiceABSTRACT
The Ras signaling pathway plays a critical role in thymopoiesis and T cell activation, but the mechanism of Ras regulation is controversial. At least one mode of Ras regulation in T cells involves the messenger diacylglycerol (DAG). RasGRP, a Ras activator with a DAG-binding C1 domain, is expressed in T cells and thymocytes. Here we show that thymi of RasGRP-null mutant mice have approximately normal numbers of immature thymocytes but a marked deficiency of mature, single-positive (CD4+CD8- and CD4-CD8+) thymocytes. In Ras signaling and proliferation assays, mutant thymocytes showed a complete lack of response to DAG analogs or T cell receptor (TCR) stimulation by antibodies. Thus, TCR and DAG are linked through RasGRP to Ras signaling.
Subject(s)
DNA-Binding Proteins/immunology , Guanine Nucleotide Exchange Factors , Receptors, Antigen, T-Cell/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology , Animals , Cell Differentiation/immunology , DNA-Binding Proteins/genetics , Gene Deletion , Gene Expression Regulation/immunology , Mice , Receptors, Antigen, T-Cell/genetics , T-Lymphocytes/cytologyABSTRACT
We recently reported the molecular cloning of a novel transforming rat brain cDNA, rbc7, that encodes a Ras activator (Ebinu et al. Science 280, p. 1082, 1998). We proposed that this cDNA is a 5' and 3' truncated version of a larger normal transcript that encodes a predicted 90-kDa protein which we called RasGRP (Ras guanyl nucleotide releasing protein). We have now studied the structure of the mouse and human sequences and confirmed our conclusions about the nature of the 5' truncation. The human gene has been localized to 15q15 by an in situ hybridization technique, while the mouse gene has been positioned on Chr 2 near thrombospondin by linkage analysis. The relatedness of RasGRP to another human sequence and a hypothetical nematode protein are also discussed.
Subject(s)
Chromosomes, Human, Pair 15 , DNA, Complementary/genetics , DNA-Binding Proteins/genetics , Guanine Nucleotide Exchange Factors , Amino Acid Sequence , Animals , Chromosome Mapping , DNA, Complementary/analysis , Humans , In Situ Hybridization , Mice , Molecular Sequence Data , Rats , Sequence Alignment , ras Proteins/geneticsABSTRACT
RasGRP, a guanyl nucleotide-releasing protein for the small guanosine triphosphatase Ras, was characterized. Besides the catalytic domain, RasGRP has an atypical pair of "EF hands" that bind calcium and a diacylglycerol (DAG)-binding domain. RasGRP activated Ras and caused transformation in fibroblasts. A DAG analog caused sustained activation of Ras-Erk signaling and changes in cell morphology. Signaling was associated with partitioning of RasGRP protein into the membrane fraction. Sustained ligand-induced signaling and membrane partitioning were absent when the DAG-binding domain was deleted. RasGRP is expressed in the nervous system, where it may couple changes in DAG and possibly calcium concentrations to Ras activation.
