Signal transduction

Signal transduction describes how a cell converts a chemical or physical stimulus into a sequence of molecular events. The proteins that detect these stimuli are usually called receptors, though sometimes the term sensor is used. When a ligand binds to a receptor—or when a signal is otherwise sensed—the receptor undergoes changes that trigger a biochemical cascade, a chain of events known as a signaling pathway. These pathways often interact with each other, forming networks that coordinate cellular responses, frequently through combinatorial signaling. At the molecular level, such responses can involve alterations in gene transcription or translation, post-translational modifications, conformational changes in proteins, or shifts in their location. These events form the fundamental controls for cell growth, proliferation, metabolism, and many other processes. In multicellular organisms, signal transduction pathways regulate cell communication in diverse ways. Each component, or node, in a signaling pathway is defined by its role relative to the initial stimulus. Ligands are called first messengers, while receptors act as signal transducers that activate primary effectors. These effectors are typically proteins and often connect to second messengers, which in turn can activate secondary effectors, and so on. Depending on the efficiency of the nodes, a signal can be amplified—a concept known as signal gain—so that a single signaling molecule can trigger a response involving hundreds to millions of molecules. Like other signals, biological signal transduction is characterized by delay, noise, feedback, feedforward, and interference, which can range from negligible to pathological. With the rise of computational biology, analyzing signaling pathways and networks has become essential for understanding cellular functions and diseases, including the signaling rewiring mechanisms that underlie responses to acquired drug resistance. **Stimuli**

Signal transduction begins with the conversion of a specific stimulus into a biochemical signal. The nature of these stimuli varies widely, from extracellular cues like the presence of epidermal growth factor (EGF) to intracellular events such as DNA damage caused by replicative telomere attrition. Traditionally, signals that reach the central nervous system are classified as senses and are transmitted from neuron to neuron through synaptic transmission. In multicellular organisms, many other intercellular signal relay mechanisms exist, including those that guide embryonic development. **Ligands**

Most signal transduction pathways involve signaling molecules, called ligands, binding to receptors and triggering events inside the cell. This binding changes the receptor’s shape, a process known as receptor activation. Most ligands are soluble molecules from the extracellular environment that bind to cell-surface receptors; examples include growth factors, cytokines, and neurotransmitters. Components of the extracellular matrix, such as fibronectin and hyaluronan, can also bind to receptors like integrins and CD44, respectively. Some molecules, such as steroid hormones, are lipid-soluble and cross the plasma membrane to reach cytoplasmic or nuclear receptors. For steroid hormone receptors, stimulation leads to binding to the promoter region of steroid-responsive genes. Not all classifications of signaling molecules consider the molecular nature of each member. For instance, odorants span a wide range of molecular classes, as do neurotransmitters, which vary in size from small molecules like dopamine to neuropeptides like endorphins. Some molecules fit into more than one class—epinephrine, for example, acts as a neurotransmitter when secreted by the central nervous system and as a hormone when secreted by the adrenal medulla. Certain receptors, such as HER2, can be activated without a ligand when overexpressed or mutated, leading to constitutive pathway activation. This may or may not be counteracted by compensation mechanisms. In HER2’s case, it acts as a dimerization partner for other epidermal growth factor receptors (EGFR), and its constitutive activation drives hyperproliferation and cancer. **Mechanical forces**

Because basement membranes are widespread in eumetazoan tissues, most cell types require attachment to survive. This has driven the evolution of complex mechanotransduction pathways that allow cells to sense the stiffness of their substratum. Such signaling is primarily orchestrated in focal adhesions, where the integrin-bound actin cytoskeleton detects changes and transmits them downstream via YAP1. Calcium-dependent cell adhesion molecules, like cadherins and selectins, can also mediate mechanotransduction. Specialized forms of mechanotransduction in the nervous system are responsible for mechanosensation, including hearing, touch, proprioception, and balance. **Osmolarity**

Controlling osmotic pressure—the difference in osmolarity between the cytosol and the extracellular medium—is critical for homeostasis at both the cellular and systemic levels. Cells detect osmotic stimuli in three ways: through changes in macromolecular crowding, ionic strength, or the properties of the plasma membrane or cytoskeleton (the latter being a form of mechanotransduction). These changes are detected by proteins called osmosensors or osmoreceptors. In humans, the best-characterized osmosensors are transient receptor potential channels found in the primary cilium of cells. In yeast, the HOG pathway has been extensively studied.