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Accession Type:
Network

Differential syn
thesis of mRNA

		Shared Object_ Differential syn thesis of mRNA
		Molecule
		Enzyme
		Reaction

compartment_1

compartment_2

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Molecule List for pathway Shared Object_Differential synthesis of mRNA (Pathway Number 1115)

	Name	Initial Conc. (uM)	Volume (fL)	Buffered
1	AC1	0.02	1000	No

2	AC1_dash_CaM	0	1000	No

3	AC2	0.015	1000	No

4	AC2_star	0	1000	No

5	active_RSK2	0	1000	No

6	ATP	5000	1000	Yes

7	Basal_CaMKIV	0.0005	1000	No

8	Basal_MAPK_active	0.0001	1000	No

9	BDNF	0	1000	Yes

10	BDNF_TrkB2_clx	0	1000	No

11	BDNF_TrkB2_star_clx	0	1000	No

12	BDNF_TrkB_clx	0	1000	No

13	BetaGamma	0	1000	No
	These exist in a nebulous sense in this model, basically only to balance the conservation equations. The details of their reassociation with G-GDP are not modeled Resting level =0.0094, stim level =.0236 from all42.g ish.
14	bRaf	0.2	1000	No

15	braf_dash_GTP_dash_Ras	0	1000	No

16	braf_dash_GTP_dash_Ras1_cplx	0	1000	No

17	braf_dash_GTP_dash_Ras2_cplx	0	1000	No

18	braf_dash_rap1_dash_GTP1_cplx	0	1000	No

19	braf_dash_Rap1_dash_GTP2_cplx	0	1000	No

20	bRaf_Rap1GTP	0	1000	No

21	C3G	0.5	1000	No

22	Ca	0.08	1000	Yes

23	CaM	20	1000	No
	There is a LOT of this in the cell: upto 1% of total protein mass. (Alberts et al) Say 25 uM. Meyer et al Science 256 1199-1202 1992 refer to studies saying it is comparable to CaMK levels.
24	CaM.PDE1	0	1000	No

25	CaM.PDE1_cplx	0	1000	No

26	CaMCa2_dash_CANAB	0	1000	No

27	CaMCa3_dash_CaNAB	0	1000	No

28	CaMCa4_dash_CaNAB	0	1000	No

29	CaMKIVc	1	1000	No

30	CaMKIVdephos_cplx	0	1000	No

31	CaMKIVphosph_cplx	0	1000	No

32	CaMKIV_CaM_Ca_c	0	1000	No

33	CaMKKdephosph_cplx	0	1000	No

34	CaMKKp	0	1000	No

35	CaMKKphosph_cplx	0	1000	No

36	CaMKK_c	0.5	1000	No
	Concentration calculated from PMID: 7883770
37	CaMKK_CaM_Ca_c	0	1000	No

38	cAMP	0	1000	No

39	cAMP_dash_PDE	0.45	1000	No

40	cAMP_dash_PDE_star	0	1000	No

41	CaM_Ca_n_dash_CaNAB	0	1000	No

42	CaM_dash_Ca	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.
43	CaM_dash_Ca2	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.
44	CaM_dash_Ca3	0	1000	No

45	CaM_dash_Ca4	0	1000	No

46	CaM_dash_GEF	0	1000	No
	See Farnsworth et al Nature 376 524-527 1995
47	CaM_dash_GEF_dash_act_dash_ras_cplx	0	1000	No

48	CaNAB	1	1000	No
	We assume that the A and B subunits of PP2B are always bound under physiol conditions. Up to 1% of brain protein = 25 uM. I need to work out how it is distributed between cytosolic and particulate fractions. Tallant and Cheung '83 Biochem 22 3630-3635 have conc in many species, average for mammalian brain is around 1 uM.
49	CaNAB_dash_Ca2	0	1000	No

50	CaNAB_dash_Ca4	0	1000	No

51	CaN_dephos_TORC1_cplx	0	1000	No

52	Ca_input	0	1000	No

53	Cbl	0.5	1000	No

54	Cbl_phospho_cplx	0	1000	No

55	Cbl_star	0	1000	No

56	craf_dash_1	0.2	1000	No

57	craf_dash_1_star	0	1000	No

58	craf_dash_1_star_star	0	1000	No
	Negative feedback by MAPK* by hyperphosphorylating craf-1* gives rise to this pool. Ueki et al JBC 269(22):15756-15761, 1994
59	craf_dash_deph_cplx	0	1000	No

60	craf_star_star_dash_deph_cplx	0	1000	No

61	CRK	1	1000	No

62	CRK_C3G	0	1000	No

63	CRK_C3G_Cbl_star_clx	0	1000	No

64	dephosph_dash_PP1_dash_I_star_cplx	0	1000	No

65	dephosph_inhib1_cplx	0	1000	No

66	dephosph_inhib1_noCaM_cplx	0	1000	No

67	dephosp_S6K_cplx	0	1000	No

68	dephos_S6K_cplx	0	1000	No

69	GAP	0.01	1000	No
	GTPase-activating proteins. See Boguski and McCormick. Turn off Ras by helping to hydrolyze bound GTP. This one is probably NF1, ie., Neurofibromin as it is inhibited by AA and lipids, and expressed in neural cells. p120-GAP is also a possible candidate, but is less regulated. Both may exist at similar levels. See Eccleston et al JBC 268(36) pp27012-19 Level=.002 16 May 2003: Increased level to 0.0036, in line with other concentration raises at the synapse.
70	GAP_dash_inact_dash_ras_cplx	0	1000	No

71	GAP_star	0	1000	No

72	GDP_dash_Ras	0.5	1000	No
	GDP bound form. See Rosen et al Neuron 12 1207-1221 June 1994. the activation loop is based on Boguski and McCormick Nature 366 643-654 93 Assume Ras is present at about the same level as craf-1, 0.2 uM. Hallberg et al JBC 269:6 3913-3916 1994 estimate upto 5-10% of cellular Raf is assoc with Ras. Given that only 5-10% of Ras is GTP-bound, we need similar amounts of Ras as Raf.
73	GEF_dash_bg_act_dash_ras_cplx	0	1000	No

74	GEF_dash_Gprot_dash_bg	0	1000	No
	Guanine nucleotide exchange factor. This activates raf by exchanging bound GDP with GTP. I have left the GDP/GTP out of this reaction, it would be trivial to put them in. See Boguski & McCormick. Possible candidate molecules: RasGRF, smgGDS, Vav (in dispute). rasGRF: Kcat= 1.2/min Km = 680 nM smgGDS: Kcat: 0.37 /min, Km = 220 nM. vav: Turnover up over baseline by 10X,
75	GEF_star	0	1000	No
	phosphorylated and thereby activated form of GEF. See, e.g. Orita et al JBC 268:34 25542-25546 1993, Gulbins et al. It is not clear whether there is major specificity for tyr or ser/thr.
76	GEF_star_dash_act_dash_ras_cplx	0	1000	No

77	Grb2	1	1000	No
	There is probably a lot of it in the cell: it is also known as Ash (abundant src homology protein I think). 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. I haven't been able to find a decent....
78	GTP_dash_Ras	0	1000	No
	Only a very small fraction (7% unstim, 15% stim) of ras is GTP-bound. Gibbs et al JBC 265(33) 20437
79	I1	1.8	1000	No
	I1 is a 'mixed' inhibitor, but at high enz concs it looks like a non-compet inhibitor (Foulkes et al Eur J Biochem 132 309-313 9183). We treat it as non-compet, so it just turns the enz off without interacting with the binding site. Cohen et al ann rev bioch refer to results where conc is 1.5 to 1.8 uM. In order to get complete inhib of PP1, which is at 1.8 uM, we need >= 1.8 uM.
80	I1_star	0.001	1000	No
	Dephosph is mainly by PP2B
81	inact_dash_GEF	0.1	1000	No
	Assume that SoS is present only at 50 nM. Revised to 100 nM to get equil to experimentally known levels.
82	inact_dash_GEF_star	0	1000	No
	Phosphorylation-inactivated form of GEF. See Hordijk et al JBC 269:5 3534-3538 1994 and Buregering et al EMBO J 12:11 4211-4220 1993
83	inhibited_dash_PKA	0	1000	No

84	Int_BDNF_TrKB2_star_clx	0.25	1000	Yes

85	MAPK	0.36	1000	No
	conc is from Sanghera et al JBC 265 pp 52 (1990) A second calculation gives 3.1 uM, from same paper. They est MAPK is 1e-4x total protein, and protein is 15% of cell wt, so MAPK is 1.5e-5g/ml = 0.36uM. which is closer to our first estimate. Lets use this. Updated 16 May 2003. Ortiz et al 1995 J Neurosci 15(2):1285-1297 provide estimates of ERK2 levels in hippocampus: 1009 ng/mg. This comes to about 3.6uM, which may still be an underestimate of synaptic levels.
86	MAPKK	0.18	1000	No
	Conc is from Seger et al JBC 267:20 pp14373 (1992) mwt is 45/46 Kd We assume that phosphorylation on both ser and thr is needed for activiation. See Kyriakis et al Nature 358 417 1992 Init conc of total is 0.18 Ortiz et al 1995 J Neurosci 15(2):1285-1297 suggest that levels are higher in hippocampus than other brain regions, and further elevated in synapses. Estimate 3x higher levels than before, at 0.5 uM. Similar results from Schipper et al 1999 Neuroscience 93(2):585-595 but again lacking in quantitation.
87	MAPKKthr_cplx	0	1000	No

88	MAPKKtyr_cplx	0	1000	No

89	MAPKK_dash_deph_cplx	0	1000	No

90	MAPKK_dash_deph_dash_ser_cplx	0	1000	No

91	MAPKK_dash_ser	0	1000	No
	Intermediately phophorylated, assumed inactive, form of MAPKK
92	MAPKK_star	0	1000	No
	MAPKK phosphorylates MAPK on both the tyr and thr residues, first tyr then thr. Refs: Seger et al JBC267:20 pp 14373 1992 The MAPKK itself is phosphorylated on ser as well as thr residues. Let us assume that the ser goes first, and that the sequential phosphorylation is needed. See Kyriakis et al Nature 358 417-421 1992
93	MAPK_active_total	0	1000	No

94	MAPK_dash_tyr	0	1000	No
	Haystead et al FEBS Lett. 306(1) pp 17-22 show that phosphorylation is strictly sequential, first tyr185 then thr183.
95	MAPK_star	0	1000	No

96	MAPK_star_dash_feedback_cplx	0	1000	No

97	MKP1_dash_thr_dash_deph_cplx	0	1000	No

98	MKP1_dash_tyr_dash_deph_cplx	0	1000	No

99	MKP_dash_1	0.015	1000	No
	MKP-1 dephosphoryates and inactivates MAPK in vivo: Sun et al Cell 75 487-493 1993. Levels of MKP-1 are regulated, and rise in 1 hour. Kinetics from Charles et al PNAS 90:5292-5296 1993. They refer to Charles et al Oncogene 7 187-190 who show that half-life of MKP1/3CH134 is 40 min. 80% deph of MAPK in 20 min Sep 17 1997: CoInit now 0.4x to 0.0032. See parm searches from jun96 on.
100	pCaMKIV_CaM_Ca_c	0	1000	No

101	pCaMKIV_CaM_Ca_c_tot	0	1000	No

102	PDE1	2	1000	No

103	PDE1_cplx	0	1000	No

104	PDE_cplx	0	1000	No

105	PDE_star_cplx	0	1000	No

106	PDK1	1	1000	No

107	phospho_S6K_cplx	0	1000	No

108	phosph_dash_AC2_cplx	0	1000	No

109	phosph_dash_PDE_cplx	0	1000	No

110	phosph_Sos_cplx	0	1000	No

111	PKA_dash_active	0	1000	No

112	PKA_dash_inhibitor	0.25	1000	No

113	PKA_dash_phosph_dash_GEF_cplx	0	1000	No

114	PKA_dash_phosph_dash_I1_cplx	0	1000	No

115	PKC_dash_active	0.01	1000	Yes

116	PKC_dash_act_dash_GEF_cplx	0	1000	No

117	PKC_dash_act_dash_raf_cplx	0	1000	No

118	PKC_dash_inact_dash_GAP_cplx	0	1000	No

119	PLCg_basal	0.0007	1000	No

120	PLC_g	0.1	1000	No

121	PLC_g_phospho_cplx	0	1000	No

122	PLC_g_phospho_cplx	0	1000	No

123	PLC_g_star	0	1000	No

124	PP1_dash_active_c	1.8	1000	No
	Cohen et al Meth Enz 159 390-408 is main source of info conc = 1.8 uM
125	PP1_dash_I1	0	1000	No

126	PP1_dash_I1_star	0	1000	No

127	PP2A	0.15	1000	Yes
	Concentration from DOQCS accession no. 90
128	PP2A_dash_dephosph_dash_I1_cplx	0	1000	No

129	PP2A_dash_dephosph_dash_PP1_dash_I_star_	0	1000	No

130	PPhosphatase2A	1	1000	No
	Refs: Pato et al Biochem J 293:35-41(93); Takai&Mieskes Biochem J 275:233-239 k1=1.46e-4, k2=1000,k3=250. these use kcat values for calponin. Also, units of kcat may be in min! revert to Vmax base: k3=6, k2=25,k1=3.3e-6 or 6,6,1e-6 CoInit assumed 0.1 uM. See NOTES for MAPK_Ras50.g. CoInit now 0.08 Sep 17 1997: Raise CoInt 1.4x to 0.224, see parm searches from jun 96 on.
131	ppRSK	0	1000	No

132	pRSK	0	1000	No

133	pTORC1	0	1000	No

134	R2	0	1000	No

135	R2C1	0	1000	No

136	R2C2	0.5	1000	No

137	R2C2_dash_cAMP	0	1000	No

138	R2C2_dash_cAMP2	0	1000	No

139	R2C2_dash_cAMP3	0	1000	No

140	R2C2_dash_cAMP4	0	1000	No

141	R2C_dash_cAMP4	0	1000	No

142	R2_dash_cAMP4	0	1000	No

143	Raf_dash_GTP_dash_Ras	0	1000	No

144	Raf_dash_GTP_dash_Ras.1_cplx	0	1000	No

145	Raf_dash_GTP_dash_Ras.2_cplx	0	1000	No

146	Raf_star_dash_GTP_dash_Ras	0	1000	No

147	Raf_star_dash_GTP_dash_Ras.1_cplx	0	1000	No

148	Raf_star_dash_GTP_dash_Ras.2_cplx	0	1000	No

149	Rap1GAP	0.012	1000	No

150	Rap1GDP	0.2	1000	No

151	Rap1GTP	0	1000	No

152	RapGAP1_cplx	0	1000	No

153	RapGAP2_cplx	0	1000	No

154	RSK	0.2	1000	No

155	S6K_phospho_cplx	0	1000	No

156	Shc	0.5	1000	No

157	Shc_phospho_cplx	0	1000	No

158	Shc_star	0	1000	No

159	Shc_star.Sos.Grb2	0	1000	No

160	SIK2	0.5	1000	No

161	SIK2_phosp_cplx	0	1000	No

162	SIK2_star	0	1000	No

163	Sos	0.1	1000	No

164	Sos.Grb2	0	1000	No

165	Sos.Ras_GEF_cplx	0	1000	No

166	Sos_star	0	1000	No

167	Sos_star.Grb2	0	1000	No

168	Src	0.02	1000	No

169	Src_phospho_cplx	0	1000	No

170	Src_star	0	1000	No

171	Sum_total_CaMKIV	0	1000	No

172	TORC1c	0.1	1000	No

173	TORC1_phso_enz_cplx	0	1000	No

174	total_PP1_acive	0	1000	No

175	TrKB	0.25	1000	No

Summed Molecule List

	Target	Inputs
1	CaM_Ca_n_dash_CaNAB	CaMCa4_dash_ CaNAB CaMCa3_dash_ CaNAB CaMCa2_dash_ CANAB
2	MAPK_active_total	MAPK_star Basal_MAPK_ active Basal_MAPK_ active
3	pCaMKIV_CaM_Ca_c_tot	pCaMKIV_CaM_Ca_ c Basal_CaMKIV
4	Sum_total_CaMKIV	pCaMKIV_CaM_Ca_ c_tot pCaMKIV_CaM_Ca_ c_tot
5	total_PP1_acive	PP1_dash_ active_c PP1_dash_ active_c

Pathway Details Molecule List Enzyme List Reaction List

Database compilation and code copyright (C) 2022, Upinder S. Bhalla and NCBS/TIFR
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