The Control Analysis of Signal Transduction - Systems Biology of Metabolic and Signaling Networks - page 44

a

Cytoplasm Nucleus

NPC

V 1 i V 2i V 3i

S
S
S

x i p

p
p

y i

V 1 i +1 V 2i +1 V 3i +1

x i +1

y i +1
y i +2

V 1 i +2 V 2i +2 V 3i +2

x i +2

.
.
.

.
.
.

V n V n V n

S

x n y n p

b c

0.5
0.4
0.3
0.2
0.1
0
-0.1
-0.2
-0.3

1

Summation over path j Summation over path j

0.8
0.6
0.4

Output

NPC

Input

Input

0.2
0

Output NPC

2 4 6 8 10 12 14 16 18 20 2 46 8 012 14 16 18 20

n n

Fig. 3.2 (a) A number of parallel nuclear hormone receptor signal transduction pathways sharing
the same nuclear pore complex (NPC). The pathways compete with each other for the NPC.
(b) Signal flux control coefficients and their sums showing control of a particular nuclear receptor
transportation flux (path j ) by its own three pathway components, i.e. by the input (leading from
the plasma membrane to close to the nuclear membrane), by the NPC itself, and by the output (the
processes leading the nuclear receptor from the inside of the nuclear membrane to the establish-
ment of the complex between DNA and the nuclear hormone). (c) The control of the flux through
that same pathway, but now by the input, NPC, and output processes of a different nuclear
hormone signal transduction pathway. Also here “Input” indicates the flux control coefficient by
the input reaction of this particular nuclear receptor [the reaction between S and X i , seen in (a)],
“Output” indicates the flux control coefficient by the output reaction of this particular nuclear
receptor (the reaction between Y i and P ), while “NPC” refers to the reactions through pore.
“Summation over path j ” gives the sum of all these three control coefficients (for many relevant
details, see Kolodkin et al. 2010 )

The cross control by any one other nuclear receptor pathway disappeared when
the total number of nuclear hormone receptors using the transport protein exceeded
6: when the same transport channel is used by a number of cargoes, the signal
transduction of any one NR systems is robust with respect to perturbations in the
concentration of any single other signal transduction. When this number of active
signal transduction pathways is lower, however, various signal transduction routes
should be expected to be highly dependent on one another, to extents that depend on
various factors, and often in nonintuitive ways. Control is 100 % but may be
distributed.
The summation laws take the place of the intuition-based but in biology faltering
concept of “the rate-limiting” step: For flux they confirm that there must be a
complete rate limitation of 1, which is in line with intuition. However in biology
this rate limitation need not reside in a single step, as confirmed experimentally by