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Cell Signaling

Notch-mediated juxtacrine signal between adjacent cells.


Graphic credit: Fred the Oysteri. The source code of this SVG is valid. This vector graphics image was created with Adobe Illustrator. – Graphic: National Institute of Health. U.S. http://ccr.cancer.gov/staff/images/1372_Fortini_178.gif, Public Domain, https://commons.wikimedia.org/w/index.php?curid=36238400


In 1999 Dr. Gunter Blobel of the Rockefeller University in New York received the Nobel Laureate in Medicine or Physiology for his discovery of this protein signal system of “ZIP codes.“


ZIP code, protein is an informal name for a molecular cell biology system of signals or “address tags“ that guide the movement of a protein within a cell. In more technical terms, protein ZIP codes** are molecular signals that direct the 1) ___ from the endoplasmic reticulum, where it is assembled, to the cytoplasm of the cell and into other cellular compartments such as the nucleus of the cell. Mutations in this molecular system of protein “ZIP codes“ have been found to cause several human genetic (hereditary) disorders, including cystic fibrosis and hyperoxaluria (a disorder that causes a special type of stone to form in the urine beginning in childhood). It is well-known that the body’s immune response depends on proper direction of cells through the bloodstream and into the tissues that need them. But exactly how this cell trafficking occurred was unknown. Studies have shown that just as ZIP codes direct mail to particular communities, special molecules that sit on cell surfaces guide the cells through the bloodstream to their tissue destinations. However, before it can slip into the target tissue, a cell exiting the bloodstream must first adhere to the vessel wall. Blood cells contain more than 100 adhesion molecules, yet only a handful of these form bonds that can admit the cell into the surrounding tissue. These so-called Goldilocks molecules possess very specific chemical and mechanical properties that enable the formation of bonds of a particular strength and duration. Adhesion cannot be too tight, or the cells will bind to the vessel 2) ___ and never let go. It also can’t be too weak, or the blood cell will just pass on by. To study this phenomenon, computer simulations we used to explore the adhesion between a blood-borne cell and a surface akin to a vessel wall. Interestingly, this technique could one day be used to design 3) ___ with tailored mechanical properties.


Cell signaling is part of any communication process that governs basic activities of cells and coordinates all cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity, as well as normal tissue homeostasis. Errors in signaling interactions and cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell 4) ___, diseases may be treated more effectively and, theoretically, artificial tissues may be created. Traditional work in biology has focused on studying individual parts of cell signaling pathways. Systems biology research helps us to understand the underlying structure of cell signaling networks and how changes in these networks may affect the transmission and flow of information (signal transduction). Such 5) ___ are complex systems in their organization and may exhibit a number of emergent properties including bi-stability and ultrasensitivity. Cell signaling has been most extensively studied in the context of human diseases and signaling between cells of a single organism. However, cell signaling may also occur between the cells of two different organisms. In many mammals, early embryo cells exchange signals with cells of the uterus. In the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells.


During mating of the yeast Saccharomyces cerevisiae, some cells send a peptide signal (mating factor pheromones) into their environment. The mating factor peptide may bind to a cell surface receptor on other 6)___ cells and induce them to prepare for mating. Cell signaling can be classified to be mechanical and biochemical based on the type of the signal. Mechanical signals are the forces exerted on the cell and the forces produced by the cell. These forces can both be sensed and responded by the cells. Biochemical signals are the biochemical molecules such as proteins, lipids, ions and gases. These signals can be categorized based on the distance between signaling and responder cells. Signaling within, between, and among cells is subdivided into the following classifications:


Intracrine signals are produced by the target cell that stay within the target cell.

Autocrine signals are produced by the target cell, are secreted, and affect the target cell itself via receptors. Sometimes autocrine cells can target cells close by if they are the same type of cell as the emitting cell. An example of this are immune cells.

Juxtacrine signals target adjacent (touching) cells. These signals are transmitted along cell membranes via protein or lipid components integral to the membrane and are capable of affecting either the emitting cell or cells immediately adjacent.

Paracrine signals target cells in the vicinity of the emitting cell. Neurotransmitters represent an example.

Endocrine signals target distant cells. Endocrine cells produce hormones that travel through the blood to reach all parts of the body.


Cells communicate with each other via direct contact (juxtacrine signaling), over short distances (paracrine signaling), or over large distances and/or scales (endocrine signaling). Some cell-cell communication requires direct cell-cell contact. Some cells can form gap junctions that connect their cytoplasm to the cytoplasm of adjacent cells. In cardiac muscle, gap junctions between adjacent cells allows for action potential propagation from the cardiac pacemaker region of the heart to spread and coordinately cause contraction of the 7) ___. The notch signaling mechanism is an example of juxtacrine signaling (also known as contact-dependent signaling) in which two adjacent cells must make physical contact in order to communicate. This requirement for direct contact allows for very precise control of cell differentiation during embryonic development.


In the worm Caenorhabditis elegans, two cells of the developing gonad each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch receptor on the adjacent cell. This activates a feedback loop or system that reduces Notch expression in the cell that will differentiate and that increases Notch on the surface of the cell that continues as a stem cell.


Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Paracrine signals such as retinoic acid target only cells in the vicinity of the emitting cell. Neurotransmitters represent another example of a paracrine signal. Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain. Estrogen can be released by the ovary and function as a 8) ___ or act locally via paracrine or autocrine signaling. Active species of oxygen and nitric oxide can also act as cellular messengers. This process is dubbed redox signaling.


In a multicellular organism, signaling between cells occurs either through release into the extracellular space, divided in paracrine signaling (over short distances) and endocrine signaling (over long distances), or by direct contact, known as juxtacrine signaling. Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling molecule. Synaptic signaling is a special case of paracrine signaling (for chemical synapses) or juxtacrine signaling (for electrical synapses) between neurons and target cells. Signaling molecules interact with a target cell as a ligand to cell surface receptors, and/or by entering into the cell through its membrane or endocytosis for intracrine signaling. This generally results in the activation of second messengers, leading to various physiological effects. Neurotransmitters are signaling molecules of the nervous system, also including neuropeptides and neuromodulators. Neurotransmitters like the catecholamines are also secreted by the endocrine system into the systemic circulation. Cytokines are signaling molecules of the immune system, with a primary paracrine or juxtacrine role, though they can during significant immune responses have a strong presence in the circulation, with systemic effect (altering iron metabolism or body temperature). Growth factors can be considered as cytokines or a different class.


Signaling molecules can belong to several chemical classes: lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins, or gases. Signaling molecules binding surface receptors are generally large and hydrophilic (e.g. TRH, vasopressin, acetylcholine), while those entering the cell are generally small and hydrophobic (e.g. glucocorticoids, thyroid hormones, cholecalciferol, retinoic acid), but important exceptions to both are numerous, and a same molecule can act both via surface receptor or in an intracrine manner to different effects. In intracrine signaling, once inside the 9) ___, a signaling molecule can bind to intracellular receptors, other elements, or stimulate enzyme activity (e.g. gasses). Hydrogen sulfide is produced in small amounts by some cells of the human body and has a number of biological signaling functions. Only two other such gases are currently known to act as signaling molecules in the human body: nitric oxide and carbon monoxide.


Cells receive information from their neighbors through a class of proteins known as receptors. Notch is a cell surface protein that functions as a 10) ___. Animals have a small set of genes that code for signaling proteins that interact specifically with Notch receptors and stimulate a response in cells that express Notch on their surface. Molecules that activate (or, in some cases, inhibit) receptors can be classified as hormones, neurotransmitters, cytokines, and growth factors, in general called receptor ligands. Ligand receptor interactions such as that of the Notch receptor interaction, are known to be the main interactions responsible for cell signaling mechanisms and communication.


** For the benefit of readers, not familiar with the United States mail system, the term “ZIP code“ refers to address codes of the U.S. Postal Service used to sort mail into geographic regions.

Sources: Scientific American; Wikipedia


ANSWERS: 1) protein; 2) wall; 3) bonds; 4) signaling; 5) networks; 6) yeast; 7) heart; 8) hormone; 9) cell; 10) receptor



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