Signalling dynamics, cell decisions, and homeostatic control in health and disease

Abstract

Cell signalling engenders cells with the capability to receive and process information from the intracellular and extracellular environments, trigger and execute biological responses, and communicate with each other. Ultimately, cell signalling is responsible for maintaining homeostasis at the cellular, tissue and systemic level. For this reason, cell signalling is a topic of intense research efforts aimed to elucidate how cells coordinate transitions between states in developing and adult organisms in physiological and pathological conditions. Here, we review current knowledge of how cell signalling operates at multiple spatial and temporal scales, focusing on how single-cell analytical techniques reveal mechanisms underpinning cell-to-cell variability, signalling plasticity, and collective cellular responses.

Figure 1

Cell signalling. a)Diagrammatic representation of signal reception, transduction, and response, exemplified by ERBB receptor tyrosine kinases and MAPK signalling. Ligand binding triggers receptor dimerisation at the plasma membrane, leading to their cytoplasmic domain phosphorylation and the recruitment of signalling complexes (not shown). ERBB activation then facilitates the exchange of GDP for GTP in small GTPases (e.g. RAS proteins), inducing the recruitment of effector kinases. Here, we depict one of the several pathways that amplify and relay the initiating signal to the nucleus, the MAPK pathway (RAF→MEK→ERK). In the nucleus, ERK phosphorylates ELK leading to transcription of target genes, biological response, and termination of the originating signal.b)Diagrammatic representation of ERBB ligand reception. ERBB1 (also known as EGFR) binds the epidermal growth factor (EGF), transforming growth factor alpha (TGFA), amphiregulin (AREG), heparin-binding EGF-like growth factor (HBEGF), betacellulin (BTC), epigen (EPGN) and epiregulin (EREG). ERBB2 has no ligand but can heterodimerise with other ERBB receptors. ERBB3 has very low kinase activity on its own but forms active dimers upon binding to neuregulins (NRG1/2). ERBB4 binds to several ligands of ERBB1/3, and NRG3/4.c)Once a molecular event (ligand binding) is transduced to a biochemical signal (RTK phosphorylation), a network of networks (here we depict MAPK, PI3K, and hippo pathways) further process the biochemical signal in space and time to trigger the most appropriate biological response.d)Signalling dynamics favour the activation of specific transcriptional programs depending on the stability of target transcripts and proteins. For example, ELK induce the transcription of FOS that is rapidly degraded. However, if ERK activation is sustained, ERK phosphorylate also FOS, leading to proliferation through Cyclin D1 (CCDN1) expression [14].

Figure 2

Cell decisions and homeostasis. a)Cellular decisions are essential during development and in adult tissues. Even excluding the hematopoietic system with its very high turnover, of the 3 trillion cells making up an adult human body, up to 40 billion die each day [40]. Turnover of cells varies significantly across tissues (being lowest in the brain and the highest in the gut and hematopoietic system); however, by the end of our lifespan, a human body might have replenished 1000 times more cells than the number of cells it has at any given time.b)Cell fates exhibit stochastic characteristics, here described by a Galton board. Cells are depicted by marbles falling onto pins (biochemical events). Each step is deterministic, but marbles eventually fall into a ‘cell fate’ box randomly following distributions determined by the geometrical configuration of the pins. Most cells are quiescent within a tissue, and an equal number of cells die and are born, on average, to maintain tissue homeostasis. Molecular cues favour one or the other cell fate, inducing tissue regeneration or leading to aberrant homeostasis.c)Genetically identical cells of the same type can thus exhibit vast cell-to-cell variability of non-genetic origin. Biochemical signals are then shifting the balance in the cellular population (in the analogy of the Galton board, the pins are moved), favouring homeostasis in healthy tissues or causing cell fate imbalances in disease (e.g. excess proliferation in cancer). Therapies aim to restore homeostasis in target tissue avoiding homeostatic disruption in others.

Figure 3

Studying signalling dynamics in space and time. a)Diagrammatic representation of MAPK network topology as determined by Santos et al. [21]. In response to EGF and NGF, ERK exhibit transient or sustained activation. Different dynamics are determined by distinct feedback mechanisms enacted by growth factor receptors, and result in different cell decisions (proliferation versus differentiation). However, each cell might respond with a different dynamic to the same stimulus. Panelb)shows MCF7 cells stably expressing the EKAREV ERK FRET-based sensor and a nuclear marker treated with 100 ng/ml EGF. The large majority of cells respond with the transient activation of ERK (red), similar to the average response (grey). However, ∼10% of cells either do not respond (yellow) or respond with sustained ERK signalling (blue). The non-responders and the sustained responders were classified as those cells that either do not cross the 1.1 FRET ratio threshold (red marks on the ordinate), or cells that raise above the marker initially but do not return below 1.1. Methods can be found in De et al. [27] c)Diagrammatic representation of optogenetic tools utilised to control cell signalling.