The different signaling molecules of multicellular organisms


There are many ways in which cells can interact with their environments. Usually these interactions involve some protein receptor either transmembrane or not, that convert these extracellular signals into intracellular biochemical events. These exchanges preside over cell development, differentiation, and cellular actions. These signals can be a result in direct cell-to-cell contact, or through other chemical signals such as chemokines or cytokines that elicit cellular responses over long or short distances. Errors or changes in these signaling networks can result in diseases, cell death, or simply a miscommunication between cells hence leading to wrong signal transmission. However these signals also have very strict and distinct regulatory elements as well that are incorporated within these signal pathways.

Most multicellular organisms have countless different signaling molecules. Frequently they are released by the signaling cell into the extracellular matrix by a process known as exocytosis and include proteins, small peptides, amino acids, steroids and several other signaling molecules. There are other routes and forms that signaling molecules can take on their journey to their target cell however, such as transmembrane proteins. These proteins are externally displayed, but remain attached to the cell membrane. A familiar example of these cell surface receptor proteins is the famous G-coupled protein receptors which are typically characterized as having seven transmembrane domains. In this case cell signaling only occurs when other cells make contact thus signaling a series of intracellular events. These direct cell-to-cell contacts are commonly seen in developmental and immune system function. Even though these cell contacts are seen throughout cell signaling, other modifications of these transmembrane proteins can occur i.e. when the extracellular portion of the transmembrane protein is cleaved. When this happens it then has the ability to work at further distances away from its origin since it then becomes a secreted signal molecule which can bind to their target receptors. No matter what the signal is the target cell responds via a receptor that is usually made up of transmembrane proteins, that binds its appropriate ligand, which then initiates a biochemical response within the target cell. The examples mentioned above are just a few general concepts that will be discussed later in detail.

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As mentioned before signaling cells secrete signal molecules into the extracellular fluid that then migrate to their target cells or they can act as local mediators. In the immune system local mediators are chemical signals (cytokines/chemokines) that activate an inflammatory response that aids in fighting an infection. Cytokines generally have the ability to signal a cell to undergo some sort of a change, while chemokines act as a chemoattractant, recruiting cells along a gradient. Generally what happens during an inflammatory response cytokines (IL-1β, TNF-α, IL-6, IL-12) and chemokines (CXCL8 specifically) are produced by macrophages and can cause numerous effect including dilation of blood vessels and an increase of adhesion molecules lining the blood vessel walls. Adhesion molecules usually bind receptors located on cell surfaces. The increase in selectins (E-selectin), integrins, and ICAMs (Intracellular adhesion molecules) on the vascular endothelium allows an increase in binding of neutrophils and monocytes. Located on these neutrophils is also the chemokine receptor CXCL8R, which is the receptor for IL-8, a potent chemical in inflammation. Once a white blood cell has bound to these receptors located on the blood vessel, it allows the white blood cell to pass through the basement membrane and into the infected area of infection. IL-1β, TNF-α, IL-6, IL-12 are also important cytokines as they recruit additional neutrophils, basophils, and T-cells, while activating NK cells. IL-12 is important because it induces the differentiation of CD4 T cells into TH1 cells. This is one way in which cells can communicate with eachother via potent chemical signaling localized to a specific area. This also illustrates the idea that a cell is programmed to respond to a specific combination of extracellular signals and uses this information to regulate cell shape and movement.

Nevertheless, inside cells there lies a complex system of signaling proteins and these systems of signaling are known as signal transduction pathways. One such pathway is the tyrosine kinase pathway that seems to be a reoccurring theme in signal transduction pathways. Since the immune system has been used as a model system for a lot of these pathways, it is only fair to use it as an example for tyrosine kinases.  During T-cell activation the T-cell receptor complex and co-receptor are associated with Src-family protein kinases, Fyn and Lck. Src family kinases generally contain SH3 and SH2 domains that interact with the kinase, preventing it from being activated. Release of either the SH2 or SH3 domain via ligand binding can activate kinase activity. However, for the T-cell to become activated antigen presenting cells "present" the antigen to immature or what can be called naive T-cells. Binding of the T-cell receptor, peptide:MHC ligand, and co-receptors clusters the TCR and CD4 molecules thus activating the intracellular T-cell signaling pathway. This clustering of the receptors aids in enhancing phosphorylation of the receptor, but the signaling networks headed by receptor tyrosine kinases appear to depend on adapter proteins to carry out efficient signaling.

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Phosphorylation is a common mechanism carried out by kinases and will generally act by either activation or deactivation of protein enzymes by adding a phosphate. Fyn or Lck, which are non-receptor tyrosine kinases, act by phosphorylating tyrosine residues on CD3ε and ζ ITAMs (Immuno-tyrosine based activation motifs) after the immature T-cell has been activated through its receptor cross-linking. This allows ZAP-70 (Zeta-chain associated protein kinase) to bind the phosphorylated ITAMs. Lck activates ZAP-70, which then activates the scaffold proteins LAT and SLP-76 through phosphorylation. Scaffold proteins help to localize pathway components to specific parts of the cell such as the plasma membrane. SLP-76 binds to phospholipase, PLC- γ, and is activated by Itk, a Tec family cytoplasmic tyrosine kinase. PLC- γ then cleaves phosphatidylinositol bisphosphate (PIP2) to yield diacylglycerol (DAG) and inositol triphosphate (IP3). This is the point at which T-cell activation branches off into three different pathways. This is common in cellular signaling since the extracellular signals a cell receives can be interpreted in several different ways. DAG can activate protein kinase C- θ, which activates transcription factor NFκB. IP3 can increase intracellular Ca2+ concentration thus activating phosphatase calcineurin which can then activate the transcription factor NFAT (nuclear factor of activated T-cells). Lastly, DAG can activate RasGRP, a guanine exchange factor, which activates a MAP kinase cascade by way of a small G protein, Ras. The Ras-induced kinase cascade Erk induces and activates Fos, which is a component of the AP-1 transcription factor. In addition to this, activation of MAP kinase cascade JNK allows phosphorylation of c-Jun, permitting it to relocate to the nucleus where it can bind with Fos, thus forming transcription factor AP-1. These transcription factors all work towards the same goal which is to stimulate the differentiation and proliferation of T-cell specific to the antigen through activating protein synthesis of IL-2, the T-cell growth factor. This is simply one example of how tyrosine kinases work in a system that has been relatively well studied. More importantly it demonstrates how an extracellular signal that was initiated by direct cell-to-cell contact can be internalized and processed within the cell all the way to the cell nucleus to initiate transcription of an important and vital cytokine involved in T-cell differentiation and proliferation. It also shows the complexity of cell signaling.

Cell signaling is also being studied in depth in developing organisms and by that it means that developmental biologists are looking for answers to questions that as how do these cells know what they are to become? What causes stem cells to differentiate? How do these cells orient themselves? How does a single cell form into tissues and organs? The immune system is a fantastic model signaling system, but it lacks the ability to demonstrate how cells can become tissues and so forth. Another well studies signaling pathway is Notch. Similarly to the tyrosine kinase pathway the Notch pathway has been studied in depth. It has been shown to be highly conserved amongst multicellular organisms and plays vital roles in neuronal growth and functioning, angiogenesis, commitment of T-cells from its common lymphoid progenitor, expansion of hematopoietic stem cells, and many others. As mentioned previously, transmembrane bound proteins have the option of being proteolytically cleaved once the extracellular domain has been bound by ligand proteins. This mechanism is important in notch signaling as the cleavage results in the release of the intracellular domain, which can then migrate directly into the cell nucleus to activate or repress gene expression. Another point to mention here is that most of the ligands are transmembrane proteins thus this signaling cascade is a result of direct cell-to-cell contact, which has been a common theme mentioned throughout this paper. These cell-to-cell contacts are extremely important to the overall scheme of cell signaling and interactions and not merely because it can activate an intracellular signal transduction cascade. . The notch/Lin-12/Glp-1 receptor family has been seen to play an extremely important role in C. elegans and Drosophila cell fates and development during embryonic development and adult life. These interactions are also important because they allow the cells to organize themselves and influence eachother. This could mean that when a neighboring expresses a trait, it can inhibit it in other cells.

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There are other signaling pathways that have been studied throughout recent years and the roles of these pathways are of increasingly greater interest especially in biomedical research. Defects in these pathways often have deleterious effects on cells and often times changes in these signaling patterns results in cancer.