Feedback loops shape cellular signals in space and time

Abstract

Positive and negative feedback loops are common regulatory elements in biological signaling systems. We discuss core feedback motifs that have distinct roles in shaping signaling responses in space and time. We also discuss approaches to experimentally investigate feedback loops in signaling systems.

Fig. 1

Ca²⁺ and chemotaxis signaling systems exhibit complex temporal and spatial dynamics. (A) Histamine-triggered cytosolic Ca²⁺ signals in a single epithelial cell. The response includes spikes, oscillations, and plateaus. pCa is the negative log of the Ca²⁺ concentration (7 and 6 correspond to 10⁻⁷ and 10⁻⁶ M, respectively). [Adapted from (28)] (B) Total internal reflection fluorescence images of a neutrophil cells stimulated by chemoattractant. Hem-1 is a regulator of actin polymerization that initially concentrates in foci. It then relocalizes as part of outwardly propagating waves of actin polarization that terminate when the leading edge is reached (denoted by arrow at 112 s). The fifth and sixth images show overlays of successive Hem-1 distributions in red, blue, and green, respectively. [Adapted from (29)]

Fig. 2

Feedback motifs have important functions in signaling systems. (A) Negative feedback can stabilize basal signaling levels, limit maximal signaling output, enable adaptive responses, or create transient signal responses. (B) Positive feedback can amplify signaling responses, alter kinetics, or create bistable switches. (C) Mixtures of positive and negative feedback can create single pulses or oscillatory signal outputs. Mixed feedbacks can also trigger local signals, self-propagating waves, or cell polarization.

Fig. 3

Addition of extra feedback to core functions can be used to integrate key signaling characteristics or enhance the robustness of important functions. (A) Combining two negative feedback loops can independently stabilize basal signaling and limit maximal signal output. (B) Adding a negative feedback loop to the oscillator in Fig. 2C can result in sharper spikes, an increased input range over which oscillations occur and an increased output frequency range. (C) A system made up of a dual fast and slow positive feedback loops can exhibit transient or persistent bistable states if the fast or both positive feedbacks are engaged.

Fig. 4

Cell signaling systems take advantage of multiple feedback loops nested in time and space to generate desired signaling responses. Schematic representations of (A) mammalian Ca²⁺ signaling for nonexcitable cells and (B) neutrophil chemotaxis. The input signal spreads from membrane-bound receptors to a network of interlinked feedback loops. Feedback loops are arranged according to the loop time constant. PLC, phospholipase C; MCU, mitochondrial Ca²⁺ uniporter; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; Dock, dedicator of cytokinesis; rec., recruitment; dep., depletion.

Fig. 5

Proposed rapid perturbation and monitoring strategy to experimentally investigate feedback loops. The shown graphs with proposed experiments use computer simulations of experiments to explain how fast perturbations and fast readouts can uncover feedback. Bold arrows denote the addition of inhibitors for the activities A, B, and C. Experiments in 1 show that the two players B and C regulate A. Experiments 2 and 3 reveal that B and C are part of a positive and a negative feedback loop, respectively.