Inverted signaling hierarchy between RAS and RAC in T-lymphocytes.
In order to generate coherent biological responses to extracellular stimuli, cells have established synergistic and antagonistic crosstalk between pathways with similar or opposing functions, respectively. Two routes cooperating in the generation of mitogenic and cytoskeletal functions are those induced by Ras and Rho/Rac GTPases. In these signaling interactions, Rho/Rac proteins have been always placed in a downstream position respect to Ras in all cell systems analysed so far. In this report, we describe that such signaling hierarchy does not apply to T-lymphocytes. Thus, we show that both Rac1 GDP/GTP exchange factors such as Vav and constitutively active versions of Rac1 can promote the effective stimulation of the Ras pathway in T-lymphocytes. The molecular link for this new type of pathway interconnectivity is RasGRP1, a diacylglycerol-dependent GDP/GTP exchange factor for Ras that translocates to the plasma membrane in a Vav- and Rac1-dependent manner. The effect of the Vav/Rac1 pathway on the Ras pathway is highly dependent on the activity of phospholipase C-gamma, the key cellular supplier of intracellular diacylglycerol. Signaling experiments suggest that this crosstalk represents a signaling strategy used by the T-cell receptor to promote robust biological responses of both the Rac/Rho and Ras pathways upon antigen engagement.
Zugaza
José L
JL
Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, University of Salamanca-CSIC, Campus Unamuno, E-37007 Salamanca, Spain.
Caloca
María J
MJ
Bustelo
Xosé R
XR
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D019169:Jurkat Cells; D008301:Maleimides / Q000494:pharmacology; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D011760:Pyrrolidinones / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D004963:Estrenes; D020662:Guanine Nucleotide Exchange Factors; D007211:Indoles; D008301:Maleimides; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011760:Pyrrolidinones; C491790:RASGRP1 protein, human; C496618:VAV1 protein, human; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D014443:Tyrosine; D011493:Protein Kinase C; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; C070515:bisindolylmaleimide I