Digital signaling and hysteresis characterize Ras activation in lymphoid cells.

“The simulations were carried out using the Gillespie algorithm ( Gillespie, 1977 ), which has been used Figure 1. A Minimal Model of the Catalytic Domain of SOS Predicts Three Possible States of Ras Activation (A) SOS’ protein domains, GEF pocket, and allosteric pocket.”

“Stochastic Simulations of the Model Shown in Figures 2 and 4 We used the Gillespie algorithm (Bortz et al., 1975; Gillespie, 1977; McAdams and Arkin, 1997) to perform stochastic simulations that effectively solve the Master equation (van Kampen, 1992) corresponding to the chemical reactions in the…”

“We adapted Hartigan’s test (Hartigan and Hartigan, 1985), which allows for a qualitative determination of whether a response in a population of cells is bimodal or unimodal.”

“Stochastic Simulations of the Model Shown in Figures 2 and 4 We used the Gillespie algorithm (Bortz et al., 1975; Gillespie, 1977; McAdams and Arkin, 1997) to perform stochastic simulations that effectively solve the Master equation (van Kampen, 1992) corresponding to the chemical reactions in the…”

“…Nationwide Children’s Hospital and Department of Pediatrics, Biophysics Graduate Program, Ohio State University, 700 Children’s Drive, Columbus, OH 43205, USA *Correspondence: aweiss@medicine.ucsf.edu (A.W.), arupc@mit.edu (A.K.C.), jeroen.roose@ucsf.edu (J.P.R.) DOI 10.1016/j.cell.2008.11.051”

“Receptor Stimulation Results in Digital Signaling with SOS and Analog Responses with RasGRP Alone Thestrengthof lymphocyte receptorstimulation impactsoutcomes (e.g., T cell activation, thymocyte development; Starr et al., 2003).”

“…is one of many nonlinear mechanisms that can result in ‘‘digital’’ responses of gene regulation programs and signaling networks (Barkai and Leibler, 2000; Bhalla and Iyengar, 1999; Elf and Ehrenberg, 2004; Ferrell, 2002; Kholodenko et al., 2002; Kussell et al., 2005; McAdams and Arkin, 1997).”

“Activated Ras proteins regulate several cellular processes by acting on many substrates to affect signaling through diverse pathways (e.g., the MAPK pathway) (Campbell et al., 1998; Mor and Philips, 2006).”

“Bistability andHysteresisProvide RasSignalingMemory during Serial Stimulation T cell activation may require integration of membrane-proximal signals from sequential contacts (each approximately 3 min in duration) that occur between T cells and antigen-presenting cells (APCs) in lymphoid tissues ( Bousso and Robey, 200…”

“The threshold potency above which strongly binding ligands negatively select thymocytes in the thymus is very sharp while the positive selection threshold is graded (Daniels et al., 2006).”

“SOS’ activity is regulated by membrane localization and is greatly accelerated upon binding of active RasGTP to a noncatalytic (allosteric) site (Margarit et al., 2003).”

“It has been suggested that digital ERK signaling, along with feedback regulation of Lck, may enable discrimination between ligands of varying potency (Altan-Bonnet and Germain, 2005).”

“…is one of many nonlinear mechanisms that can result in ‘‘digital’’ responses of gene regulation programs and signaling networks (Barkai and Leibler, 2000; Bhalla and Iyengar, 1999; Elf and Ehrenberg, 2004; Ferrell, 2002; Kholodenko et al., 2002; Kussell et al., 2005; McAdams and Arkin, 1997).”

“It will of interest to investigate how analog (RasGRP) and digital (SOS) mechanisms of Ras activation occur in time and space as well as whether recently observed spatial nanoclustering of active Ras proteins (Tian et al., 2007) is influenced by positive feedback regulation of Ras activation.”

“…Nationwide Children’s Hospital and Department of Pediatrics, Biophysics Graduate Program, Ohio State University, 700 Children’s Drive, Columbus, OH 43205, USA *Correspondence: aweiss@medicine.ucsf.edu (A.W.), arupc@mit.edu (A.K.C.), jeroen.roose@ucsf.edu (J.P.R.) DOI 10.1016/j.cell.2008.11.051”

“Activated Ras proteins regulate several cellular processes by acting on many substrates to affect signaling through diverse pathways (e.g., the MAPK pathway) (Campbell et al., 1998; Mor and Philips, 2006).”

“Recent studies have suggested that T cell activation in such circumstances requires integration of interrupted serial encounters with APCs bearing cognate ligands (Henrickson et al., 2008).”

“Cell 136, 337–351, January 23, 2009 ª2009 Elsevier Inc. 339 profitably to study biological systems that exhibit multistability (Elf and Ehrenberg, 2004; Kussell et al., 2005; McAdams and Arkin, 1997).”

“Two families of RasGEFs are well studied in lymphocytes: RasGRP1 and RasGRP3 (Ras guanyl nucleotide release protein) and SOS1 and SOS2 (Son of Sevenless) (Ebinu et al., 2000; Roose et al., 2005, 2007).”

“in Lymphoid Cells”

“in Lymphoid Cells”

“During this period the stimulus is ‘‘off,’’ and active Ras levels decline because phosphatases act on pLAT (Figure 4) causing SOS to disengage from the membrane, RasGAPs reduce RasGTP levels during the time that the stimulus is ‘‘off,’’ etc. Suppose that during the next encounter of this T cell with an APC it encounte…”

“Two families of RasGEFs are well studied in lymphocytes: RasGRP1 and RasGRP3 (Ras guanyl nucleotide release protein) and SOS1 and SOS2 (Son of Sevenless) (Ebinu et al., 2000; Roose et al., 2005, 2007).”

“Bistability andHysteresis ProvideRasSignalingMemory during Serial Stimulation T cell activation may require integration of membrane-proximal signals from sequential contacts (each approximately 3 min in duration) that occur between T cells and antigen-presenting cells (APCs) in lymphoid tissues (Bousso and Robey, 2003…”

“RasGTP levels in WT DT40 cells were sensitive to PP2 inhibition at the initiation of BCR stimulation.”

“Activated ZAP-70 phosphorylates the adaptor molecule LAT, which recruits both PLCg and Grb2/SOS.”

“Basal RasGRP1-mediated activation of Ras is not subject to feedback regulation but can ‘‘ignite’’ the SOS feedback loop ( Roose et al., 2007 ) by providing RasGTP that can bind SOS’ allosteric pocket and increase its activity 75-fold.”

“A GEF, RasGRF, which is structurally related to RasGRP, is not dependent on feedback regulation by Ras (Freedman et al., 2006).”

“JPRM441 cells were transfected with GFP together with SOScat, SOScat-W729E (allosteric pocket mutant), H-RasG59E38 (RasGTP mimetic), H-Ras, or combinations thereof.”

“Therefore, we used a chicken DT40 B cell line in which pertinent genes have been genetically inactivated (Oh-hora et al., 2003).”

“Recruitment of SOS to the plasma membrane results in conformational changes that relieve this inhibition and allow RasGDP to bind to SOS’ catalytic site (Corbalan-Garcia et al., 1998).”

“…Nationwide Children’s Hospital and Department of Pediatrics, Biophysics Graduate Program, Ohio State University, 700 Children’s Drive, Columbus, OH 43205, USA *Correspondence: aweiss@medicine.ucsf.edu (A.W.), arupc@mit.edu (A.K.C.), jeroen.roose@ucsf.edu (J.P.R.) DOI 10.1016/j.cell.2008.11.051”

“…Nationwide Children’s Hospital and Department of Pediatrics, Biophysics Graduate Program, Ohio State University, 700 Children’s Drive, Columbus, OH 43205, USA *Correspondence: aweiss@medicine.ucsf.edu (A.W.), arupc@mit.edu (A.K.C.), jeroen.roose@ucsf.edu (J.P.R.) DOI 10.1016/j.cell.2008.11.051”

“Including this feature would lead to sharper cellular responses (Prasad et al., 2009).”

“Phospholipase A2 is, however, not expressed in T and B lymphocytes (Gilbert et al., 1996).”

“, 2001), immunology (Das et al., 2009), developmental biology (Sha et al.”

“MEK, and ultimately the MAP kinase ERK [9].”

“…of ERK to respond in an all-or-none manner has been noted Frequency-Modulated ERK Signaling in Proliferation (Altan-Bonnet and Germain, 2005; Das et al., 2009; Markevich et al., 2004; Qiao et al., 2007; Sturm et al., 2010), we show that transitions between the ‘‘on’’ and ‘‘off’’ state are…”