Branched Motifs Enable Long-Range Interactions in Signaling Networks through Retrograde Propagation

Abstract

Branched structures arise in the intra-cellular signaling network when a molecule is involved in multiple enzyme-substrate reaction cascades. Such branched motifs are involved in key biological processes, e.g., immune response activated by T-cell and B-cell receptors. In this paper, we demonstrate long-range communication through retrograde propagation between branches of signaling pathways whose molecules do not directly interact. Our numerical simulations and experiments on a system comprising branches with JNK and p38MAPK as terminal molecules respectively that share a common MAP3K enzyme MEKK3/4 show that perturbing an enzyme in one branch can result in a series of changes in the activity levels of molecules “upstream” to the enzyme that eventually reaches the branch-point and affects other branches. In the absence of any evidence for explicit feedback regulation between the functionally distinct JNK and p38MAPK pathways, the experimentally observed modulation of phosphorylation amplitudes in the two pathways when a terminal kinase is inhibited implies the existence of long-range coordination through retrograde information propagation previously demonstrated in single linear reaction pathways. An important aspect of retrograde propagation in branched pathways that is distinct from previous work on retroactivity focusing exclusively on single chains is that varying the type of perturbation, e.g., between pharmaceutical agent mediated inhibition of phosphorylation or suppression of protein expression, can result in opposing responses in the other branches. This can have potential significance in designing drugs targeting key molecules which regulate multiple pathways implicated in systems-level diseases such as cancer and diabetes.

Signaling cascades transmit information downstream and upstream but unlikely simultaneously

“…Similar conclusions have been experimentally observed on a two-branch MAP-Kinase cascade, allowing to activate responses of JNK and p38MAPK (equivalent to cycles 2 and 3 in the previous description) [ 17 ]. Here the authors termed the notion of retroactive signaling by retrograde propagation.…”

“…Applying a perturbation at any level of the cascade (such as sequestration of the active protein or over-expression of a phosphatase) would have implications both downstream and upstream of the disturbance level due to retroactivity. This result, that was experimentally validated ([ 10 , 15 – 17 ]), indicates that a kinase cascade is a bidirectional device regarding information transmission. However, how likely is it that a cascade transmits information upstream?…”

Emergent memory in cell signaling: Persistent adaptive dynamics in cascades can arise from the diversity of relaxation time-scales

“…The terminal kinase in this cascade, i.e., MAPK, transmits the signal further downstream by phosphorylating various proteins, including transcription regulators 9 . Extensive investigations into the asymptotic dynamical behavior of the cascade have contributed towards an in-depth understanding of several emergent features including ultrasensitivity 10 , and oscillations 11 , 12 that arise through retrograde propagation of activity 13 – 15 or explicit feedback 16 . One of the striking features of the cascade is the occurrence of bistability, which allows the system to switch between two possible states corresponding to low and high activity 12 , 17 – 20 .…”

Emergent memory in cell signaling: Persistent adaptive dynamics in cascades can arise from the diversity of relaxation time-scales

“…The terminal kinase in this cascade, i.e., MAPK, transmits the signal further downstream by phosphorylating various proteins including transcription regulators [9]. Extensive investigations into the steadystate behavior of the cascade have contributed towards an in-depth understanding of several emergent features including ultrasensitivity [10], and oscillations [11,12] that arise through retrograde propagation of activity [13,14]. One of the striking features of the cascade is the occurrence of bistability which allows the system to switch between two possible states corresponding to low and high activity [12,[15][16][17][18].…”