The biphasic behavior of incoherent feed‐forward loops in biomolecular regulatory networks

Abstract

An incoherent feed-forward loop (FFL) is one of the most-frequently observed motifs in biomolecular regulatory networks. It has been thought that the incoherent FFL is designed simply to induce a transient response shaped by a 'fast activation and delayed inhibition'. We find that the dynamics of various incoherent FFLs can be further classified into two types: time-dependent biphasic responses and dose-dependent biphasic responses. Why do the structurally identical incoherent FFLs play such different dynamical roles? Through computational studies, we show that the dynamics of the two types of incoherent FFLs are mutually exclusive. Following from further computational results and experimental observations, we hypothesize that incoherent FFLs have been optimally designed to achieve distinct biological function arising from different cellular contexts. Additional Supporting Information may be found in the online version of the article.

Biphasic responses in multi-site phosphorylation systems

“…Indeed, the biphasic response results in an 'optimal' range of stimulus for downstream effects and may be desirable for different reasons. Biphasic responses can arise due to scaffolds, or incoherent feed-forward pathways [41,42], and are often associated with these factors. It is interesting to find this capability built into the basic multi-site modification mechanism, and not requiring additional mechanisms such as scaffolds or other regulation.…”

Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling

“…I1-FFLs are also known to regulate biphasic responses where the output levels (in this case Gata2) depend on the input dose (Notch intensity; Kim et al, 2008). By computer modeling, it has been demonstrated that I1-FFLs regulate time-or dose-dependent biphasic behaviors in a mutually exclusive manner (Kim et al, 2008), and further work is needed to address whether Gata2 regulation by Notch and HES follows one of these two models. Ki67 (1:500; Novocastra) were also used.…”

Phosphorylation of residues inside the SNARE complex suppresses secretory vesicle fusion

“…Incoherent feed‐forward circuits are formed when a single signaling protein induces two opposing pathways that activate and inhibit the same cell response (Mangan & Alon, 2003). This ubiquitous circuit motif allows cells to shape the time course of functional outputs (Kim et al , 2008; Ma et al , 2009). …”