Table 1.

TNFR1 model A

	Reaction			Formula and parameters (s -1 )						Remarks
1 1	TNFR1	→	TRADD	k 1	*	TNFR1	k 1	=	5e-3	Activation of TRADD by TNFR1
2 2	TRADD	→	cIAP1/2	k 2	*	TRADD	k 2	=	2e-2	Formation of Complex 1 containing TRADD, cIAP1/2, TRAF2, TRAF5, RIP1 and the TAB/TAK complex
3 3	cIAP1/2	→	TRAF2	k 3	*	cIAP1/2	k 3	=	1e-2
4 4	cIAP1/2	→	TRAF5	k 4	*	cIAP1/2	k 4	=	8e-3
5 5	TRAF2	→	RIP1	k 5	*	TRAF2	k 5	=	1e-3
6 5	TRAF5	→	RIP1	k 6	*	TRAF5	k 6	=	1e-3
7 6	TRADD	→	TRAF6	k 7	*	TRADD	k 7	=	2e-2	Activation of TRAF6 by TRADD
8 5	TRAF6	→	RIP1	k 8	*	TRAF6	k 8	=	1e-4	Activation of RIP1 and TAK1 complex by TRAF6
9 7	TRAF6	→	TAK1 complex	k 9	*	TRAF6	k 9	=	1.3e-4
10 8	RIP1	→	LUBAC	k 10	*	RIP1	k 10	=	7e-3	Complex 1 ubiquitination by LUBAC and SHARPIN
11 9	RIP1	→	SHARPIN	k 11	*	RIP1	k 11	=	7e-3
12 7	LUBAC	→	TAK1 complex	k 12	*	LUBAC	k 12	=	1e-1
13	SHARPIN	→	IKK complex	k 13	*	SHARPIN	k 13	=	1e-2	Activation of IKK complex by Complex 1
14	TAK1 complex	→	IKK complex	k 14	*	TAK1 complex	k 14	=	1e-1
15 10	IKK complex	→	IκBα	k 15	*	IKK complex	k 15	=	1e-2	Phosphorylation of IκBα by IKK
16	IκBα	→	NF-κBc	k 16	*	IκBα	k 16	=	8e-3	Degradation of IκBα forms NF-κB
17	NF-κBc	→	NF-κBn	k 17	*	NF-κBc	k 17	=	1.7e-2	Translocation of NF-κB to nucleus
18	TAK1 complex	→	MKK1/2	k 18	*	TAK1 complex	k 18	=	1.5e-3	Activation of MAP kinases kinases by TAK1 complex
19 11	TAK1 complex	→	MKK3/6	k 19	*	TAK1 complex	k 19	=	1e-2
20	TAK1 complex	→	MKK4/7	k 20	*	TAK1 complex	k 20	=	1e-2
21	MKK1/2	→	ERK	k 21	*	MKK1/2	k 21	=	5e-3	Activation of MAP kinases
22 12	MKK3/6	→	p38	k 22	*	MKK3/6	k 22	=	5e-3
24	MKK4/7	→	JNK	k 23	*	MKK4/7	k 23	=	5e-3
24	p38	→	p38n	k 24	*	p38	k 24	=	5e-2	Translocation of MAP kinases into nucleus
25	JNK	→	JNKn	k 25	*	JNK	k 25	=	5e-2
26	ERK	→	ERKn	k 26	*	ERK	k 26	=	5e-3
27	p38n	→	AP1	k 27	*	p38n	k 27	=	1e-2	Activation of AP1 by MAP kinases
28	ERKn	→	AP1	k 28	*	ERKn	k 28	=	1e-2
29	JNKn	→	AP1	k 29	*	JNKn	k 29	=	1e-2
30	AP1	→	GI promoter	k 30	*	AP1	k 30	=	1e-1	Promoter binding of AP1 and NF-κB for group I genes
31	NF-κBn	→	GI promoter	k 31	*	NF-κBn	k 31	=	5e-3
32	G1 promoter	→	GI pre-mRNA	k 32	*	GI promoter	k 32	=	1e-2	Group I genes transcription, splicing (1 step) and decay
33	GI pre-mRNA	→	GI mRNA	k 33	*	GI pre-mRNA	k 33	=	5e-2
34	GI mRNA	→	GI mRNA decay	k 34	*	GI mRNA	k 34	=	2e-3
35 13	AP1	→	GII promoter	k 35	*	AP1	k 35	=	1.1e-2	Promoter binding of AP1 and NF-κB for group II genes
36	NF-κBn	→	GII promoter	k 36	*	NF-κBn	k 36	=	4e-3
37	GII promoter	→	GII pre-mRNA/1	k 37	*	GII promoter	k 37	=	2e-3	Group II genes transcription, splicing (2 steps) and decay
38	GII pre-mRNA/1	→	GII pre-mRNA/2	k 38	*	GII pre-mRNA/1	k 38	=	5e-2
39	GII pre-mRNA/2	→	GII mRNA	k 39	*	GII pre-mRNA/2	k 39	=	5e-2
40 13	GII mRNA	→	GII mRNA decay	k 40	*	GII mRNA	k 40	=	1.2e-4
41	AP1	→	GIII promoter	k 41	*	AP1	k 41	=	5e-3	Promoter binding of AP1 and NF-κB for group III genes
42	NF-κBn	→	GIII promoter	k 42	*	NF-κBn	k 42	=	1e-4
43	GIII promoter	→	GIII pre-mRNA/1	k 43	*	GIII promoter	k 43	=	1e-1	Group III genes transcription, splicing (3 steps) and decay
44	GIII pre-mRNA/1	→	GIII pre-mRNA/2	k 44	*	GIII pre-mRNA/1	k 44	=	4e-4
45	GIII pre-mRNA/2	→	GIII pre-mRNA/3	k 45	*	GIII pre-mRNA/2	k 45	=	1e-3
46	GIII pre-mRNA/3	→	GIII mRNA	k 46	*	GIII pre-mRNA/3	k 46	=	2e-4
47	GIII mRNA	→	GIII mRNA decay	k 47	*	GIII mRNA	k 47	=	2e-5
48	GI mRNA	→	X1	k 48	*	GI mRNA	k 48	=	1e-5	Feedback processes via group I genes or NF-κB
49	NF-κBn	→	X1	k 49	*	NF-κBn	k 49	=	5e-1	Steps of the secondary feedback processes (cytosolic or autocrine signaling):
50	X1	→	X2	k 50	*	X1	k 50	=	2e-3
51	X2	→	X3	k 51	*	X2	k 51	=	2e-3
52	X3	→	X4	k 52	*	X3	k 52	=	2e-3
53	X4	→	X5	k 53	*	X4	k 53	=	2e-3
54	X5	→	X6	k 54	*	X5	k 54	=	2e-3
55	X6	→	X7	k 55	*	X6	k 55	=	2e-3	• expression (e.g. translation)
56	X7	→	X8	k 56	*	X7	k 56	=	2e-3	• transport (e.g. secretion)
57	X8	→	X9	k 57	*	X8	k 57	=	2e-3	• signaling (e.g. receptor binding, activation of transcription factors)
58	X9	→	X10	k 58	*	X9	k 58	=	2e-3
59	X10	→	X11	k 59	*	X10	k 59	=	2e-3
60	X11	→	X12	k 60	*	X11	k 60	=	2e-3
61	X12	→	X13	k 61	*	X12	k 61	=	2e-3
62	X13	→	X14	k 62	*	X13	k 62	=	2e-3
63	X14	→	IκBα	k 63	*	X14	k 63	=	2e-3	IκBα feedback activation
64	X14	→	Y	k 64	*	X14	k 64	=	1e-5	Group III feedback activation via transcription factor Y
65	Y	→	GIII promoter	k 65	*	Y	k 65	=	2e-3

(1–12): in-silico knock-out conditions are performed by setting parameter values (k _i ) to 0 for targeted reactions in TRADD KO (1), cIAP1/2 KO (2), TRAF2 KO (3), TRAF5 KO (4) TRAF2/5 DKO (3,4), RIP KO (5), TRAF6 KO (6), TAK1 complex KO (7), LUBAC KO (8), SHARPIN KO (9), IκBα KO (10), MKK3/6 KO (11) and p38 KO (12). (13) Kinetics of Group II mRNA transcription and decay processes were refitted after adding feedback (without feedback: k ₃₅ = 7e-3, k ₄₀ = 1.2e-5). Bold italic fonts (reactions 48–65) indicate additional feedback activation pathways required for group III continuous activation. * indicates the multiplication sign.