| |
Name | Pathway Name /
Pathway No. | Accession
Type | Initial
Conc.
(uM) | Volume
(fL) | Buffered | Sum Total Of |
| 1 | Sos*.Grb2 | Sos
Pathway No. 78 | Network | 0 | 1000 | No | - |
| | Inactive complex of Sos* with Grb2 due to phosphorylation of the Sos. See Porfiri and McCormick 1996 JBC 271(10):5871. |
| 2 | Grb2 | Sos
Pathway No. 78 | Network | 1 | 1000 | No | - |
| | There is probably a lot of it in the cell: it is also known as Ash (abundant src homology protein). Also Waters et al JBC 271:30 18224 1996 say that only a small fraction of cellular Grb is precipitated out when SoS is precipitated. As most of the Sos seems to be associated with Grb2, it would seem like there is a lot of the latter. Say 1 uM. This would comfortably saturate the SoS. |
| 3 | Sos.Grb2 | Sos
Pathway No. 78 | Network | 0 | 1000 | No | - |
| | For simplicity I treat the activation of Sos as involving a single complex comprising Sos, Grb2 and Shc*. This is reasonably documented: Sasaoka et al 1994 JBC 269(51):32621-5 Chook et al JBC 1996 271(48):30472 |
| 4 | Sos* | Sos
Pathway No. 78 | Network | 0 | 1000 | No | - |
| | Phosphorylated form of SoS. Nominally this is an inactivation step mediated by MAPK, see Profiri and McCormick 1996 JBC 271(10):5871. I have not put this inactivation in this pathway so this molecule currently only represents a potential interaction point. |
| 5 | Sos | Sos
Pathway No. 78 | Network | 0.1 | 1000 | No | - |
| | I have tried using low (0.02 uM) initial concs, but these give a very flat response to EGF stim although the overall activation of Ras is not too bad. I am reverting to 0.1 because we expect a sharp initial response, followed by a decline. |
| 6 | DAG | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | Baseline in model is 11.661 uM. DAG is pretty nasty to estimate. In this model we just hold it fixed at this baseline level. Data sources are many and varied and sometimes difficult to reconcile. Welsh and Cabot 1987 JCB 35:231-245: DAG degradation Bocckino et al JBC 260(26):14201-14207: hepatocytes stim with vasopressin: 190 uM. Bocckino et al 1987 JBC 262(31):15309-15315: DAG rises from 70 to 200 ng/mg wet weight, approx 150 to 450 uM. Prescott and Majerus 1983 JBC 258:764-769: Platelets: 6 uM. Also see Rittenhouse-Simmons 1979 J Clin Invest 63. Sano et al JBC 258(3):2010-2013: Report a nearly 10 fold rise. Habenicht et al 1981 JBC 256(23)12329-12335: 3T3 cells with PDGF stim: 27 uM Cornell and Vance 1987 BBA 919:23-36: 10x rise from 10 to 100 uM. Summary: I see much lower rises in my PLC models, but the baseline could be anywhere from 5 to 100 uM. I have chosen about 11 uM based on the stimulus -response characteristics from the Schaechter and Benowitz paper and the Shinomura et al papers. |
| 7 | AA | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | Arachidonic Acid. This messenger diffuses through membranes as well as cytosolically, has been suggested as a possible retrograde messenger at synapses. |
| 8 | MAPK* | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | This molecule is phosphorylated on both the tyr and thr residues and is active: Seger et al 1992 JBC 267(20):14373 The rate consts are from two sources: Combine Sanghera et al JBC 265(1) :52-57 with Nemenoff et al JBC 93 pp 1960 to get k3 = 10, k2 = 40, k1 = 3.25e-6 |
| 9 | Glu | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | Varying the amount of (steady state) glu between .01 uM and up, the final amount of G*GTP complex does not change much. This means that the system should be reasonably robust wr to the amount of glu in the synaptic cleft. It would be nice to know how fast it is removed. Schoepp et al 1990 TIPS 11:508-515 give a range of Glu EC50 from rat brain in the range 120 to 1000 uM. Nicoletti 1986 PNAS 83:1931-1935 and Schoepp and Johnson 1989 J Neurochem 53:1865-1870 give an off time of at least 30 sec. |
| 10 | BetaGamma | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | The betagamma subunits of Gq. This is an approximation to the possible combinations of betagamma subunits. Here they are all treated as a single pool. |
| 11 | G*GTP | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | Activated G protein. Berstein et al indicate that about 20-40% of the total Gq alpha should bind GTP at steady stimulus. |
| 12 | G*GDP | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | This should correctly be called GDP.G_alpha. The name is preserved for backward compatibility reasons. |
| 13 | MKP-1 | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0.0032 | 1000 | No | - | |
| | MKP-1 dephosphorylates and inactivates MAPK in vivo: Sun et al Cell 75 487-493 1993. See Charles et al PNAS 90:5292-5296 1993 and Charles et al Oncogene 7 187-190 for half-life of MKP1/3CH is 40 min. 80% deph of MAPK in 20 min The protein is 40 KDa. The levels are MKP-1 are highly variable, as it is induced depending on MAPK activity. This selected value is well below its induced peak, but sufficiently high so that MAPK will not go into a runaway activation state. |
| 14 | PPhosphatase2A | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0.224 | 1000 | No | - | |
| | Refs: Pato et al Biochem J 293:35-41(93); CoInit values span a range depending on source. Pato et al 1993 Biochem J 293:35-41 and Cohen et al 1988 Meth Enz 159:390-408 estimate 80 nM from muscle Zolneierowicz et al 1994 Biochem 33:11858-11867 report levels of 0.4 uM again from muscle, but expression is also strong in brain. Our estimate of 0.224 is between these two. There are many substrates for PP2A in this model, so I put the enzyme rate calculations here: Takai&Mieskes Biochem J 275:233-239 have mol wt 36 KDa. They report Vmax of 119 umol/min/mg i.e. 125/sec for k3 for pNPP substrate, Km of 16 mM. This is obviously unreasonable for protein substrates. For chicken gizzard myosin light chan, we have Vmax = 13 umol/min/mg or about k3 = 14/sec. Pato et al 1993 Biochem J 293:35-41 report caldesmon: Km = 2.2 uM, Vmax = 0.24 umol/min/mg. They do not think caldesmon is a good substrate. Calponin: Km = 14.3, Vmax = 5. Our values approximate these. |
| 15 | PKA-active | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | The free catalytic subunit. |
| 16 | CaM-Ca4 | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | The four-calcium-bound form of CaM. It is the active form for most reactions. |
| 17 | Shc*.Sos.Grb2 | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | This three-way complex is one of the main GEFs for activating Ras. |
| 18 | PP1-active | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 1.8 | 1000 | No | - | |
| | Cohen et al Meth Enz 159 390-408 is main source of info concentration of enzyme = 1.8 uM |
| 19 | CaM-Ca3 | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | The TR1 end now begins to bind Ca. This form has 2 Ca's on the TR2 end, and one on the TR1. |
| 20 | CaM-TR2-Ca2 | Shared_Object_
Synaptic_
Network
Pathway No. 70Network | 0 | 1000 | No | - | |
| | This is the intermediate where the TR2 end (the high-affinity end) has bound the Ca but the TR1 end has not. |
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