In general terms, the purpose of cell signaling is to translate a particular stimulus into some kind of action by the cell. This typically involves some form of receptor protein that associates with a series of intracellular proteins which are able to transmit the signal to other parts of the cell and induce a terminal effect. In many cases the signaling events will impact transcription factors (TFs) which will ultimately result in changes to gene expression, but other physiological effects are possible such as cytoskeletal rearrangement, release of intracellular vesicles, or metabolic reprogramming.
In many cases these functional readouts can be somewhat taken for granted.
Uses of Cell Signaling in Mammalian Cells
Maintaining Homeostasis: Many cell types are responsible for monitoring and regulating some aspect of their environment. For instance, pancreatic beta cells release insulin in response to elevated blood glucose levels, promoting the uptake of glucose by cells and thereby regulating blood sugar levels. Similarly, circulating cytokine signals can direct the differentiation of hematopoietic stem and progenitor cells in the bone marrow. These broader homeostatic functions are ultimately reliant on appropriate intracellular responses from individual cells.
Coordinating Growth and Development: During embryonic development, precise cell signaling ensures the proper formation of many structures. Gradients of growth factors must be translated into specific fate decisions and the timing of these events is often critical. Many signals used in embryonic development remain relevant in adult stem cells which contribute to tissue turnover and repair.
Response to External Stimuli: Cells must rapidly adapt to changes in their environment. For example, immune cells respond to pathogens using multiple different receptor types, each recognizing a specific type of antigen. Selecting the appropriate immune response is critical to limiting infection while preventing excessive tissue damage or accidental reaction to self-antigen.
Cell-Cell Communication: Multicellular organisms rely on cell signaling to maintain proper functions within and between tissues. Feedback loops exist between many different cell types, and can be mediated by either membrane-bound signals (for close proximity signaling) or by ligands secreted into wider circulation. Either way, the cross-talk between disparate cell types is crucial for the function of complex multi-organ systems.
Apoptosis (Cell Death): Signaling pathways are also involved in programmed cell death, or apoptosis. This process is crucial for tissue turnover, as unrestrained cell death poses many problems for mature tissues. One major concern is the antigenicity of dead cell fragments, which might otherwise indicate to the immune system that a lytic infection is present. Apoptosis prevents self-antigen release, and the debris can be cleared noninflammatory processes.
Core Components of a Signaling Pathway
There are multiple pieces to every signaling pathway that must be present for full function. While the specifics are variable between pathways, there are some common features that are worth reviewing to provide orientation in future articles.
Receptor Proteins: Most pathways start with some type of transmembrane receptor protein with the ability to bind a cognate ligand. The process of ligand binding induces a specific change to the receptor, whether a conformational change or by inducing dimerization (or higher-order aggregation). Some receptors have intracellular domains which can interact with downstream signaling proteins, while others require association with adapter proteins to transmit signals.
Second Messengers: Some signaling pathways utilize non-protein molecules in the cell as signaling intermediates. These take multiple forms, including cyclic AMP, calcium ions (stored in the endoplasmic reticulum to create a voltage potential), and phosphorylated membrane lipids such as inositol. Signaling events will result in the increased or decreased concentration of second messengers which can then have a dramatic impact on multiple pathways.
Protein Kinases and Phosphatases: The majority of the signaling proteins that will be covered by the later articles of this series are either kinases (which add phosphate groups to other molecules) or phosphatases (which remove phosphate groups). These phosphate modifications lead to specific functional changes to the target protein, and cascades of kinases activating other kinases are common features in mammalian signaling. It is important to note that most phosphorylated proteins do not need to be degraded to terminate their activity.
Ubiquitin Ligases and the Proteasome: While not directly involved in many pathways, protein degradation plays a very important role in cell signaling. Continuous degradation of signaling proteins like β-catenin is a key regulatory feature of those systems, with activation of the pathway leading to an accumulation of the signaling proteins.
Transcription Factors and Other Transcriptional Machinery: The “goal” of many signaling pathways is to somehow alter the state of the cell, and that usually begins with a change to the gene transcription profile. Many signaling pathways result in the modification of one or more TFs which can result in their translocation from the cytosol to the nucleus and/or alter the protein-protein interactions that contribute to initiation/inhibition of transcription.
Common Signaling Pathways in this Series
Many signals converge on conserved pathways in the cell, and each of the important categories will be covered in individual detail. As each of those articles are published a link will be added to take you there.
MAPK (Mitogen-Activated Protein Kinase) Pathway:
- Function: Regulates cell proliferation, differentiation, and response to extracellular signals.
- Key Players: MAPK kinases, MAPKs, and various growth factor receptors.
- Activation: Typically initiated by growth factors binding to RTKs, leading to a phosphorylation cascade.
PI3K-Akt (Phosphoinositide 3-Kinase-Akt) Pathway:
- Function: Regulates cell survival, growth, and metabolism.
- Key Players: PI3K, Akt (protein kinase B), and mTOR.
- Activation: Triggered by RTKs or GPCRs, leading to Akt activation and cell growth.
Wnt Signaling Pathway:
- Function: Controls cell fate, tissue development, and stem cell maintenance.
- Key Players: Wnt ligands, Frizzled receptors, and β-catenin.
- Activation: Wnt ligands binding to Frizzled receptors trigger β-catenin accumulation and target gene expression.
Notch Signaling Pathway:
- Function: Regulates cell differentiation and tissue patterning.
- Key Players: Notch receptors and Delta or Jagged ligands.
- Activation: Ligand-receptor interactions lead to proteolytic cleavage of Notch and nuclear translocation for target gene activation.
NF-κB (Nuclear Factor-kappa B) Pathway:
- Function: Controls immune response, inflammation, and cell survival.
- Key Players: NF-κB transcription factor and IκB inhibitory proteins.
- Activation: Typically initiated by cytokines or pathogen-associated molecular patterns (PAMPs).
Hedgehog Signaling Pathway:
- Function: Regulates embryonic development, tissue regeneration, and stem cell maintenance.
- Key Players: Hedgehog ligands, Patched receptors, and Smoothened receptors.
- Activation: Ligand binding relieves Patched-mediated Smoothened inhibition, leading to target gene expression.
TGF-β (Transforming Growth Factor-beta) Pathway:
- Function: Controls cell growth, differentiation, and tissue repair.
- Key Players: TGF-β ligands, TGF-β receptors, and Smad transcription factors.
- Activation: Ligand binding triggers Smad phosphorylation and translocation to the nucleus to regulate gene expression.
Conclusions and Further Reading
As we have seen, cells utilize signaling events to control a wide array of functions which are important locally and to the organism more broadly. It is tempting to simply understand cell biology in terms of stimulus and functional response relationships, but this ignores the significant contribution of all the molecules in between the receptor and the transcription factor. This disconnect is a scientifically dangerous one, and this series sets out to bridge that gap by first changing our focus from the functional response to the activation of a conserved pathway (which ultimately leads to a functional response). Building from here we will work our way towards the cell surface, eventually discussing many key cell surface receptors. By the time we get there, though, we should have enough contextual knowledge to appreciate the nuances of receptor activation in each context.
See you on the next one! Stay curious!
Further Reading:
