Mitogen Activated Protein (MAP) kinase kinase kinase ( MAPKKK , MKKK , M3K , or, MAP3K ) is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase . Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis . The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:
36-477: Several classes of MAPKKK exist, and all of them are upstream of MAP kinases. There are three main classes of MAP Kinases and are regulated by their respective MAPKKKs. These MAP kinases include the extracellular regulated kinases (ERKs), the c-Jun N-terminal Kinases (JNKs), and the p38 MAP kinase. The ERKs are regulated by the Raf family of MAPKKKs and are responsible for cell growth, differentiation, and meiosis. Perhaps
72-470: A variety of intracellular cascades. Receptors and ligands are common upstream signaling molecules that dictate the downstream elements of the signal pathway. A plethora of different factors affect which ligands bind to which receptors and the downstream cellular response that they initiate. The extracellular type II and type I kinase receptors binding to the TGF-β ligands. Transforming growth factor-β (TGF-β)
108-427: A bistable organelle at the apical end of each cell. The organelle consists of microtubules and microfilaments in mechanical opposition. It responds to local mechanical perturbations caused by morphogenetic movements. These then trigger traveling embryonic differentiation waves of contraction or expansion over presumptive tissues that determine cell type and is followed by cell differentiation. The cell state splitter
144-462: A consequence of changes in cell adhesive and contractile properties. Following epithelial-mesenchymal transition, cells can migrate away from an epithelium and then associate with other similar cells in a new location. In plants, cellular morphogenesis is tightly linked to the chemical composition and the mechanical properties of the cell wall. During embryonic development, cells are restricted to different layers due to differential affinities. One of
180-557: A like-to-like manner: E-cadherin (found on many epithelial cells) binds preferentially to other E-cadherin molecules. Mesenchymal cells usually express other cadherin types such as N-cadherin. The extracellular matrix (ECM) is involved in keeping tissues separated, providing structural support or providing a structure for cells to migrate on. Collagen , laminin , and fibronectin are major ECM molecules that are secreted and assembled into sheets, fibers, and gels. Multisubunit transmembrane receptors called integrins are used to bind to
216-609: A specific cascade is used. These scaffolds have a binding site for the MAPKKK, MAPKK, and MAPK, ensuring that the signal occurs rapidly. Because MAPKKKs are involved in a wide range of cell responses occurring both in the cytoplasm and the nucleus, a mutation in these genes can cause several diseases. Over-expression of the MAPKKK upstream of the ERK 1/2 MAPK and an increase in epidermal growth factor receptor (EGFR) can lead to tumor formation, such as triple negative breast cancer. A mutation in
252-408: A technique which has been highly optimized in recent years due to its use in machine learning . This model was limited to the generation of pictures, and is thus bi-dimensional. A similar model to the one described above was subsequently extended to generate three-dimensional structures, and was demonstrated in the video game Minecraft , whose block-based nature made it particularly expedient for
288-502: A tissue level, ignoring the means of control, morphogenesis arises because of cellular proliferation and motility. Morphogenesis also involves changes in the cellular structure or how cells interact in tissues. These changes can result in tissue elongation, thinning, folding, invasion or separation of one tissue into distinct layers. The latter case is often referred as cell sorting . Cell "sorting out" consists of cells moving so as to sort into clusters that maximize contact between cells of
324-479: A tumor necrosis factor. Since MAPKKK are activated through the addition of a phosphates group on a serine/threonine residue, they are deactivated by a phosphatase. A common phosphatase used in ASK-1 regulation is PP5. MAPKKKs contain a docking domain which is different from their active site that allows them to contact another substrate. Additionally, several scaffolds are used in the MAPKKK cascade in order to ensure that
360-475: A wide variety of cell types. The effects of transforming growth factor-β (TGF-β) are determined by cellular context. There are three kinds of contextual factors that determine the shape the TGF-β response: the signal transduction components, the transcriptional cofactors and the epigenetic state of the cell. The different ligands and receptors of TGF-β are significant as well in the composition signal transduction pathway. The type II receptors phosphorylate
396-415: Is a superfamily of cytokines that play a significant upstream role in regulating of morphogenesis , homeostasis , cell proliferation, and differentiation. The significance of TGF-β is apparent with the human diseases that occur when TGF-β processes are disrupted, such as cancer, and skeletal, intestinal and cardiovascular diseases. TGF-β is pleiotropic and multifunctional, meaning they are able to act on
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#1732790819093432-437: Is an example of highly abnormal and pathological tissue morphogenesis. Morphogenesis also describes the development of unicellular life forms that do not have an embryonic stage in their life cycle. Morphogenesis is essential for the evolution of new forms. Morphogenesis is a mechanical process involving forces that generate mechanical stress, strain, and movement of cells, and can be induced by genetic programs according to
468-604: Is either stress or growth factors. This includes mitogens, inflammatory cytokines, ER stress, oxidative stress, UV radiation, and DNA damage. Most MAPKKKs are activated through GPCR 's where the signal from the stimuli binds to the GPCR and the GTPase activity of the g-protein activates the downstream MAPKKK. Other mechanisms for MAPKKK do exist. For instance, the MAPKKK ASK-1 is activated by a receptor-tyrosine kinase specific for
504-590: Is followed is based upon the type of signal, the strength of binding, and the length of binding. MEKK1 activates MAPK8/JNK by phosphorylation of its activator SEK1( MAP2K4 ). MAP3K3 directly regulates the MAPK8/JNK and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively; it does not regulate the p38 pathway. MAP3K7 (TAK1) participates in regulation of transcription by transforming growth factor-beta ( TGF-beta ). The most upstream stimuli that activate MAPKKK
540-463: Is highly variable based on cellular context. TGF-β downstream signaling cascade includes regulation of cell growth, cell proliferation , cell differentiation , and apoptosis . Morphogenesis Morphogenesis (from the Greek morphê shape and genesis creation, literally "the generation of form") is the biological process that causes a cell , tissue or organism to develop its shape. It
576-444: Is one of three fundamental aspects of developmental biology along with the control of tissue growth and patterning of cellular differentiation . The process controls the organized spatial distribution of cells during the embryonic development of an organism . Morphogenesis can take place also in a mature organism, such as in the normal maintenance of tissue by stem cells or in regeneration of tissues after damage. Cancer
612-424: Is the so-called French flag model , developed in the sixties. Improvements in computer performance in the twenty-first century enabled the simulation of relatively complex morphogenesis models. In 2020, such a model was proposed where cell growth and differentiation is that of a cellular automaton with parametrized rules. As the rules' parameters are differentiable, they can be trained with gradient descent ,
648-503: The bacteriophage (phage) T4 virion , the morphogenetic proteins encoded by the phage genes interact with each other in a characteristic sequence. Maintaining an appropriate balance in the amounts of each of these proteins produced during viral infection appears to be critical for normal phage T4 morphogenesis. Phage T4 encoded proteins that determine virion structure include major structural components, minor structural components and non-structural proteins that catalyze specific steps in
684-484: The plasma membrane . Individual members of the TGF-β family bind to a certain set of characteristic combination of these type I and type II receptors. The type I receptors can be divided into two groups, which depends on the cytoplasmic R-Smads that they bind and phosphorylate. The first group of type I receptors (Alk1/2/3/6) bind and activate the R-Smads, Smad1/5/8. The second group of type I reactors (Alk4/5/7) act on
720-412: The spiral shell of a snail , Turing correctly predicted a mechanism of morphogenesis, the diffusion of two different chemical signals, one activating and one deactivating growth, to set up patterns of development, decades before the formation of such patterns was observed. The fuller understanding of the mechanisms involved in actual organisms required the discovery of the structure of DNA in 1953, and
756-618: The ECM. Integrins bind extracellularly to fibronectin, laminin, or other ECM components, and intracellularly to microfilament -binding proteins α-actinin and talin to link the cytoskeleton with the outside. Integrins also serve as receptors to trigger signal transduction cascades when binding to the ECM. A well-studied example of morphogenesis that involves ECM is mammary gland ductal branching. Tissues can change their shape and separate into distinct layers via cell contractility. Just as in muscle cells, myosin can contract different parts of
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#1732790819093792-582: The JNK or p38 family of MAPK or their MAPKKK upstream precursors can result in Alzheimer's disease . This is also seen when there is too much oxidative stress in the brain, causing these MAPKs to undergo more apoptosis and destroy brain cells. MLK, a type of MAPKKK, are associated with Parkinson's disease and inhibitors to the MLK proteins have been shown to treat Parkinson's disease. The MAPKKK pathways and specifically
828-459: The R-Smads, Smad2/3. The phosphorylated R-Smads then form complexes and the signals are funneled through two regulatory Smad (R-Smad) channels (Smad1/5/8 or Smad2/3). After the ligand-receptor complexes phosphorylate the cytoplasmic R-Smads, the signal is then sent through Smad 1/5/8 or Smad 2/3. This leads to the downstream signal cascade and cellular gene targeting. TGF-β regulates multiple downstream processes and cellular functions. The pathway
864-567: The alveoli. Branching morphogenesis is also evident in the ductal formation of the mammary gland . Primitive duct formation begins in development , but the branching formation of the duct system begins later in response to estrogen during puberty and is further refined in line with mammary gland development. Cancer can result from disruption of normal morphogenesis, including both tumor formation and tumor metastasis . Mitochondrial dysfunction can result in increased cancer risk due to disturbed morphogen signaling. During assembly of
900-620: The best characterized MAP3K are the members of the oncogenic RAF family (RAF1, BRAF, ARAF), which are effectors of mitogenic ras signaling and which activate the ERK1/2 (MAPK3/MAPK1) pathway , through activation of MEK1(MAP2K1) and MEK2(MAP2K2). The JNKs are regulated by the MEKK 1/4, MLK 2/3, and ASK 1 MAPKKKs. The p38 MAPK is regulated by MEKK 1-4 and TAO 1/2 families of MAPKKKs and is responsible for inflammation, apoptosis, cell differentiation, and cell cycle regulation. The determination for what cascade
936-421: The cytoplasm to change its shape or structure. Myosin-driven contractility in embryonic tissue morphogenesis is seen during the separation of germ layers in the model organisms Caenorhabditis elegans , Drosophila and zebrafish . There are often periodic pulses of contraction in embryonic morphogenesis. A model called the cell state splitter involves alternating cell contraction and expansion, initiated by
972-436: The development of molecular biology and biochemistry . Several types of molecules are important in morphogenesis. Morphogens are soluble molecules that can diffuse and carry signals that control cell differentiation via concentration gradients. Morphogens typically act through binding to specific protein receptors . An important class of molecules involved in morphogenesis are transcription factor proteins that determine
1008-865: The fate of cells by interacting with DNA . These can be coded for by master regulatory genes , and either activate or deactivate the transcription of other genes; in turn, these secondary gene products can regulate the expression of still other genes in a regulatory cascade of gene regulatory networks . At the end of this cascade are classes of molecules that control cellular behaviors such as cell migration , or, more generally, their properties, such as cell adhesion or cell contractility. For example, during gastrulation , clumps of stem cells switch off their cell-to-cell adhesion, become migratory, and take up new positions within an embryo where they again activate specific cell adhesion proteins and form new tissues and organs. Developmental signaling pathways implicated in morphogenesis include Wnt , Hedgehog , and ephrins . At
1044-452: The morphogenesis sequence. Phage T4 morphogenesis is divided into three independent pathways: the head, the tail and the long tail fibres as detailed by Yap and Rossman. An approach to model morphogenesis in computer science or mathematics can be traced to Alan Turing 's 1952 paper, "The chemical basis of morphogenesis", a model now known as the Turing pattern . Another famous model
1080-581: The over-expression of cascades of JNK and p38 are also involved in Crohn's disease and polycystic kidney disease . Inhibitors of these pathways help in treating the symptoms of the diseases. Upstream and downstream (transduction) The upstream signaling pathway is triggered by the binding of a signaling molecule, a ligand , to a receiving molecule, a receptor . Receptors and ligands exist in many different forms, and only recognize/bond to particular molecules. Upstream extracellular signaling transduce
1116-412: The same type. The ability of cells to do this has been proposed to arise from differential cell adhesion by Malcolm Steinberg through his differential adhesion hypothesis . Tissue separation can also occur via more dramatic cellular differentiation events during which epithelial cells become mesenchymal (see Epithelial–mesenchymal transition ). Mesenchymal cells typically leave the epithelial tissue as
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1152-593: The spatial patterning of cells within tissues. Abnormal morphogenesis is called dysmorphogenesis . Some of the earliest ideas and mathematical descriptions on how physical processes and constraints affect biological growth, and hence natural patterns such as the spirals of phyllotaxis , were written by D'Arcy Wentworth Thompson in his 1917 book On Growth and Form and Alan Turing in his The Chemical Basis of Morphogenesis (1952). Where Thompson explained animal body shapes as being created by varying rates of growth in different directions, for instance to create
1188-594: The strongest adhesion move to the center of a mixed aggregates of cells. Moreover, cell-cell adhesion is often modulated by cell contractility, which can exert forces on the cell-cell contacts so that two cell populations with equal levels of the same adhesion molecule can sort out. The molecules responsible for adhesion are called cell adhesion molecules (CAMs). Several types of cell adhesion molecules are known and one major class of these molecules are cadherins . There are dozens of different cadherins that are expressed on different cell types. Cadherins bind to other cadherins in
1224-434: The type I receptors; the type I receptors are then enabled to phosphorylate cytoplasmic R-Smads, which then act as transcriptional regulators. Signaling is initiated by the binding of TGF-β to its serine/threonine receptors. The serene/threonine receptors are the type II and type I receptors on the cell membrane. Binding of a TGF-β members induces assembly of a heterotetrameric complex of two type I and two type II receptors at
1260-428: The ways this can occur is when cells share the same cell-to- cell adhesion molecules . For instance, homotypic cell adhesion can maintain boundaries between groups of cells that have different adhesion molecules. Furthermore, cells can sort based upon differences in adhesion between the cells, so even two populations of cells with different levels of the same adhesion molecule can sort out. In cell culture cells that have
1296-431: Was first proposed to explain neural plate morphogenesis during gastrulation of the axolotl and the model was later generalized to all of morphogenesis. In the development of the lung a bronchus branches into bronchioles forming the respiratory tree . The branching is a result of the tip of each bronchiolar tube bifurcating, and the process of branching morphogenesis forms the bronchi, bronchioles, and ultimately
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