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Biological crosstalk refers to instances in which one or more components of one
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
(ECM) and the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is co ...
.


Crosstalk between signalling pathways

One example of crosstalk between proteins in a signalling pathway can be seen with
cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
's (cAMP) role in regulating cell proliferation by interacting with the
mitogen-activated protein A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
(MAP) kinase pathway. cAMP is a compound synthesized in cells by adenylate cyclase in response to a variety of extracellular signals. cAMP primarily acts as an intracellular second messenger whose major intracellular receptor is the cAMP-dependent protein kinase (PKA) that acts through the phosphorylation of target proteins. The signal transduction pathway begins with ligand-receptor interactions extracellularly. This signal is then transduced through the membrane, stimulating adenylyl cyclase on the inner membrane surface to catalyze the conversion of ATP to cAMP. ERK, a participating protein in the MAPK signaling pathway, can be activated or inhibited by cAMP. cAMP can inhibit ERKs in a variety of ways, most of which involve the cAMP-dependent protein kinase (PKA) and the inhibition of Ras-dependent signals to Raf-1. However, cAMP can also stimulate cell proliferation by stimulating ERKs. This occurs through the induction of specific genes via phosphorylation of the transcription factor CREB by PKA. Though ERKs do not appear to be a requirement for this phosphorylation of CREB, the MAPK pathway does play into crosstalk again, as ERKs are required to phosphorylate proteins downstream of CREB. Other known examples of the requirement of ERKs for cAMP-induced transcriptional effects include induction of the prolactin gene in pituitary cells, and of the dopamine beta-hydroxylate gene in pheochromocytomal cells (PC12). A number of diverse mechanisms exist by which cAMP can influence ERK signaling. Most mechanisms involving cAMP inhibition of ERKs uncouple Raf-1 from Ras activation through direct interaction of PKA with Raf-1 or indirectly through PKA interaction with the GTPase Rap1 (see figure 1). PKA may also negatively regulate ERKs by the activation of PTPases. Mechanisms for the activation of ERKs by cAMP are even more varied, usually including Rap1 or Ras, and even cAMP directly.


Transmembrane crosstalk

Crosstalk can even be observed across membranes. Membrane interactions with the extracellular matrix (ECM) and with neighboring cells can trigger a variety of responses within the cell. However, the topography and mechanical properties of the ECM also come to play an important role in powerful, complex crosstalk with the cells growing on or inside the matrix. For example,
integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...
-mediated
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is co ...
assembly and even
cell motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
are affected by the physical state of the ECM. Binding of the α5β1 integrin to its ligand (
fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as coll ...
) activates the formation of fibrillar adhesions and
actin filaments Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cells that form part of the cytoskeleton. They are primarily composed of polymers of actin, but are modified by and interact with numerous other p ...
. Yet, if the ECM is immobilized, matrix reorganization of this kind and formation of fibrillar adhesions is inhibited. In turn, binding of the same integrin (α5β1) to an immobilized fibronectin ligand is seen to form highly phosphorylated focal contacts/ focal adhesion (cells involved in matrix adhesion) within the membrane and reduces cell migration rates In another example of crosstalk, this change in the composition of focal contacts in the cytoskeleton can be inhibited by members of yet another pathway: inhibitors of myosin light-chain kinases or Rho kinases, H-7 or ML-7, which reduce cell contractility and consequently motility. (see figure 2).


Crosstalk in lymphocyte activation

A more complex, specific example of crosstalk between two major signaling pathways can be observed with the interaction of the cAMP and MAPK signaling pathways in the activation of
lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ada ...
. In this case, components of the cAMP pathway directly and indirectly affect MAPK signaling pathway meant to activate
genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
involving
immunity Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity de ...
and lymphocytes. Newly formed cAMP is released from the
membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...
and diffuses across the intracellular space where it serves to activate PKA. The
catalytic Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
subunit of PKA must bind four molecules of cAMP to be activated, whereupon activation consists of cleavage between the regulatory and catalytic subunits. This cleavage in turn activates PKA by exposing the catalytic sites of the C subunits, which can then phosphorylate an array of proteins in the cell. In lymphocytes, the intracellular levels of cAMP increase upon antigen-receptor stimulation and even more so in response to
prostaglandin E Prostaglandin E is a family of naturally occurring prostaglandins that are used as medications. Types include: * Prostaglandin E1 also known as alprostadil * Prostaglandin E2 also known as dinoprostone Both types are on the World Health Orga ...
and other
immunosuppression Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
agents. In this case, cAMP serves to inhibit immunity players. PKA type I colocalizes with the
T-cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
and
B-cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...
antigen receptors and causes inhibition of T- and B-cell activation. PKA has even been highlighted as a direct inducer of genes contributing to immunosuppression. Additionally, the cAMP pathway also interacts with the MAPK pathway in a more indirect manner through its interaction with hematopoietic PTPase (HePTP). HePTP is expressed in all leukocytes. When overexpressed in T-cells, HePTP reduces the transcriptional activation of the
interleukin-2 Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16  kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible fo ...
promoter typically induced by the activated T-cell receptor through a MAPK signaling cascade. The way that HePTP effectively inhibits the MAPK signaling is by interacting with the MAP kinases Erk1, Erk2, and p38 through a short sequence in HePTP's non-catalytic N terminus termed the kinase interaction motif (KIM)., The highly-specific binding of Erk and p38 to this subunit of HePTP results in rapid inactivation of the signaling cascade (see figure 3). Yet, since both HePTP and Erk are
cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
, it is reasonable to conclude that there exists a mechanism for the inhibition of Erk by HePTP to cease in order to allow for the translocation of activated Erk to the
nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: * Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...
. Indeed, like in many other cases of protein-protein interaction, HePTP appears to be phosphorylated by Erk and p38 at the sites Thr45 and Ser72. Importantly though, a third phosphorylation site in the non-catalytic N terminus (the KIM region) of HePTP has been found—one that is phosphorylated to a much higher stoichiometry by the cAMP pathway, in yet another instance of crosstalk between the cAMP and MAPK pathways. Phosphorylation of this third site by PKAs from the cAMP pathway inhibits binding of MAP kinases to HePTP and thereby upregulates the MAPK/ERK signaling cascade. The MAPK pathway, through Ras, Raf, Mek, and Erk, shows low activity in the presence of unphosphorylated (active) HePTP. However, activation the cAMP pathway stimulates the activation of PKA, which in turn phosphorylates HePTP at Ser23. This prevents HePTP from binding to Erk and frees the MAPK pathway from inhibition, allowing downstream signaling to continue (see figure 4). Moreover, studies involving smooth muscle cells from the atrium of the heart have shown that PKA can reduce the activation of MAP kinases in response to platelet-derived growth factor ( PDGF) by phosphorylating the kinase c-Raf. Thus, it seems plausible that PKA in the cAMP pathway could even be further involved in the regulation of lymphocyte activation not only by inhibiting the antigen-receptor MAPK signal pathway at its final stage, but even further upstream.


Notes and references

{{Reflist Signal transduction