“Change begets change. Nothing propagates so fast. ” (C.J.H. Dickens, The Life and Adventures of Martin Chuzzlewit)

Cells have the capacity to emit as well as to receive, decode, and transmit information efficiently, and to integrate new signals. Any cell experiences numerous, simultaneous or successive, events that result from permanent, regulated communications between it and adjoining cells and the extracellular matrix as well as remote controller cells of the nervous and endocrine systems, in addition to immunocytes. Cell signaling not only governs basic cellular activities, but also coordinates actions of cell populations.

Plasmalemmal receptors that initiate signaling can be: (1) enzymes, such as receptor kinases and phosphatases, membrane-tethered guanylate cyclases, NADPH oxidases, and tranfer ATPases; (2) proteins coupled to enzymes, such as G-protein-coupled receptors and pseudo-receptor kinases; (3) some types of cytokine receptors; (4) ions channels; (5) adhesion molecules; and (6) mass-transfer receptors, which transport a first chemical messenger; in addition to (7) specialized plasmalemmal nanodomain components that participate in endocytosis, during which signaling can be launched.

Members of these various groups of plasmalemmal receptors can cluster and form the so-called transducisome. Any plasmalemmal molecule can undergo a strain with a more or less deep conformational change when stretched, but most of them do not send any signal. Among plasmalemmal receptors, some are mechanosensitive. Mechanical stress deforms and activates mechanosensitive molecules that can then initiate signaling by stimulating, directly or not, a second messenger.

Once the plasmalemmal receptor is activated, a cascade of chemical reactions triggers either the release of stored signaling mediators for a rapid response or gene transcription for a delayed reaction. Both event types lead to specific cell responses. In general, initial steps of signaling pathways occurs at the cell cortex upon recruitment of appropriate effectors for optimal efficiency.

Scaffold proteins serve as assembly platforms for enzymes, their regulators, and their substrates. Therefore, they have an active role in effector enzyme activation. Scaffold proteins bind to at least 2 other signaling proteins. They help to localize signaling molecules to specific cell regions. They restrain the non-specific access of enzymes to unwanted substrates. Some scaffold proteins can have other functions, such as coordination of positive and negative feedback signals or protection of activated proteins from inactivation. Scaffold proteins can have distinct functions under different conditions. Multiple scaffold–receptor complexes may exist simultaneously, thereby launching both overlapping and distinct cellular events. On the other hand,adaptor proteins (accessory proteins) connect proteins in order to form multimolecular complexes that do not have enzymatic activity.

Alternative splicing of messenger RNA defines different reconnections of transcribed exons, thereby generating various types of mature RNA transcripts from a given primary transcripts (splice variants). This process then leads to the synthesis of multiple stable protein isoforms, more or less functional, encoded by a single gene, under selective constraints (Vol. 1 – Chap. 5. Protein Synthesis). Although many alternative transcript variants are produced in the cell, only a small amount leads to the synthesis of stable proteins. Heterogeneous nuclear ribonucleoproteins are involved in the regulation of alternative splicing. Alternative isoforms of 10 among 26 possible primary transcript types that encode heterogeneous nuclear ribonucleoproteins can be detected [1]. Among all types of splice variants, a large number of alternative isoforms is created from homologous exons. An other large number of alternative isoforms can simply arise from the insertion or deletion of a single amino acid or a small number of residues. Small resulting differences in protein sequence and structure may cause minor changes in function. Nevertheless, alternative splicing influences the binding affinity of proteins for their partners.

Intracellular cascades of chemical reactions requires many mediators. Each signaling node can include not only a given mediator (i.e., a signaling effector) and its affector(s), but also one or several docking or scaffolding proteins. Signaling mediators — effectors, scaffolds, and adaptors — can have various names according to their discovery framework and investigation history. This book aims at presenting an exhaustive list of intracellular mediators with their effects.

In the framework of mathematical modeling, once collected the participants of a target signaling pathway and their role known, the main components of this pathway are selected without neglecting a major element, but eliminating all minor contributors. This selection enables to develop a simplified, tractable, and representative mathematical model of the explored biological process.

Signaling pathways determine cell functioning for given missions that generate specific molecular effects. The knowledge of expression patterns of various involved signaling components — from extracellular messengers that bind to their cognate receptors to trigger a reaction cascade, during which a set of effectors is activated — and the bulk activity of signaling pathways can be discovered from loss- and gain-of-function analysis and from disorders that originate from gene mutations and disturb signaling.

According to their structural and functional features, signaling mediators are classified in multiple categories. Major mediator categories are exhibited in many chapters. A first chapter presents lipid mediators and their modifying enzymes. The following chapters focus on sets of cytoplasmic protein tyrosine, serine/threonine, and dual-specificity kinases, with an emphasis on mitogen-activated protein kinase modules that include protein Ser/Thr and dual-specificity kinases, as well as protein phosphatases, in addition to others major mediators involved in cardiovascular and respiratory physiology and pathophysiology. The final chapter gives examples of several selected signaling pathways, such as those involving typical second messengers (cyclic adenosine and guanosine monophosphates and calcium ions), as well as those primed by adhesion and matrix molecules and those involved in oxygen sensing, insulin stimulation, angiogenesis, and mechanotransduction.

Among all mechanisms that contribute to cell events by modifying the structure and function of signaling mediators, phosphorylation and dephosphorylation correspond to a major process that allows cells to modulate protein activity either at their surfaces or inside their cytoplasms in response to environmental stimuli, such as conformational, positional, and nutritional signals, as well as other regulatory cues.