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Very Detailed Information for Signal Pathway

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The signal pathway means that when a certain reaction occurs in a cell, the signal transmits a message from outside the cell to the cell, and the cell responds according to the information. The signal pathway was first traced back to 1972, but it was called signal transmission at that time. In 1980, M. Rodbell referred to signal transduction in a review, and the concept has since been widely used. A signaling pathway is a series of enzymatic reaction pathways that can exert extracellular molecular signals through the cell membrane and into cells. These extracellular molecular signals (called ligands) include hormones, growth factors, cytokines, neurotransmitters, and other small molecule compounds.


How does the signal in the cell pass when the ligand specifically binds to the receptor in the cell membrane or cell?

The various biochemical pathways in the cell are composed of a series of different proteins that perform different physiological and biochemical functions. The regulation of downstream protein activity (including activation or inhibition) by upstream proteins in each signaling pathway is primarily accomplished by the addition or removal of phosphate groups, thereby altering the stereoconfiguration of downstream proteins. Therefore, the major members of the signaling pathway are protein kinases and phosphatases, which are capable of rapidly altering and restoring the conformation of downstream proteins. Receiving an external signal from a cell receptor to finally making a comprehensive response is not only a signal transduction process, but more importantly, a process of gradually amplifying the external signal. Receptor proteins convert extracellular signals into intracellular signals, which are amplified, dispersed, and regulated by signal cascades, resulting in a comprehensive array of cellular responses, including regulation of downstream gene expression, changes in intracellular enzyme activity, and cellular bone architecture. Type and changes in DNA synthesis, etc. These changes are not all caused by one type of signal, but different reactions can be produced by different combinations of several signals.


First, when the signal molecules are lipids such as cholesterol, they can easily cross the cell membrane and bind to the target receptor in the cytoplasm;

Second, when the signal molecules are polypeptides, they can only bind to receptors such as proteins on the cell membrane. These receptors are mostly transmembrane proteins. Through conformational changes, signals are transmitted from the extracellular domain to the domain within the membrane, and then Acting with the next level of receptors, the next level of pathway is activated by modification such as phosphorylation.


Common signal path

NF-κB signal

NF-kB (nuclear factor-kappa B) is a transcription factor found in the nuclear extract of B lymphocytes in 1986. It binds specifically to the enhancer B sequence GGGACTTTCC of the immunoglobulin kappa light chain gene and promotes κ. Light chain gene expression, hence the name. It is a member of the Rel family of eukaryotic transcription factors and is widely found in various mammalian cells [1]. To date, five NF-kB/Rel family members have been found in mammalian cells, which are RelA (ie, p65), RelB, C-Rel, p50/NF-kB1 (ie, p50/RelA) and p52/NF. -kB2. These members all have a Rel homology domain (RHD) of approximately 300 amino acids. This highly conserved domain mediates the formation of a homologous or heterodimer of the Rel protein, which is also a region of specific binding of NF-kB to the DNA sequence of the target gene.

The activation process of NF-kB in cells is finely regulated. Normally, NF-kB in the cytoplasm is inactivated and binds to the inhibitory protein of NF-kB to form a trimer complex. When TNF-a signaling, inflammatory factors, and external stimuli such as LPS and ultraviolet rays are present, cytokines bind to TNF receptors on the surface of cell membranes, and TNF receptors multimerize and interact with TRADD molecules in the cytoplasm. TRADD recruits TRAF (TNFR-associated factor) and kinase RIP (receptor interacting protein), and signals are transmitted by RIP to IKK (IkB kinase). IKK plays a very important role in the NF-kB signaling pathway, and although it is different in the upstream signal path, it eventually aggregates into IKK. IKK consists of three subunits a, b and g. IKK as a kinase phosphorylates the Ser32 and Ser36 residues of the a subunit of IkB and the Ser19 and Ser23 residues of the b subunit. IkB is then dissociated from the p50/p65/IkB heterotrimer and degraded by proteasome after ubiquitination. Thus, NF-kB, which is inhibited by IkB, is exposed to its nuclear localization signals (NLS), rapidly entering the nucleus from the cytoplasm, and binding to specific sequences on the DNA in the nucleus to initiate or enhance transcription of related genes.

2. JAK-STAT signaling pathway

1) JAK and STAT proteins

The JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines discovered in recent years, and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. Compared with other signaling pathways, this signaling pathway is relatively simple to transfer. It consists of three components, namely tyrosine kinase-related receptor, tyrosine kinase JAK and transcription factor STAT.

2) JAK-STAT signaling pathway

The transfer of the JAK-STAT signaling pathway is relatively simple compared to other signaling pathways. The signaling process is as follows: Binding of cytokines to the corresponding receptor causes dimerization of the receptor molecule, which allows the JAK kinases coupled to the receptor to be close to each other and activated by interactive tyrosine phosphorylation. After JAK activation, the tyrosine residues on the catalytic receptor are phosphorylated, and then these phosphorylated tyrosine sites form a "docking site" with the surrounding amino acid sequence, and contain the SH2 domain. STAT protein was recruited to this "parking site." Finally, the kinase JAK catalyzes the phosphorylation of the STAT protein bound to the receptor, and the activated STAT protein enters the nucleus in the form of a dimer to bind to the target gene and regulate gene transcription. It is worth mentioning that a JAK kinase can be involved in the signal transduction of many cytokines. A cytokine signaling pathway can also activate multiple JAK kinases, but cytokines have certain choices for activated STAT molecules. Sex. For example, IL-4 activates STAT6, while IL-12 specifically activates STAT4.

3.Ras, PI (3)K and mTOR signals

With the completion of the sequencing of the human genome, hundreds of protein kinases have been discovered. Based on their structural similarities, these kinases can be divided into multiple protein families that play important biological functions in cell proliferation, growth, differentiation, and apoptosis. Ras, PI(3)K and mTOR are a class of protein kinases closely related to cell proliferation. The normal growth of eukaryotic cells is limited by the nutrients provided by the surrounding environment. Ras and PI (3)K signaling play a key role in regulating cell growth by regulating the downstream molecule mTOR.

In most human tumor cells, key mutations in the Ras and PI (3)K signaling pathways have undergone significant mutations. The reason is that if this signal pathway is mutated, it will lead to cell survival and growth no longer limited by environmental conditions such as nutrients, and then induce cell cancer. It is worth noting that some tumor suppressors, such as TSC1, TSC2 and LKB1, attenuate the intensity of the mTOR signaling pathway under nutrient-deficient conditions. Correspondingly, inactivation mutations in TSC1, TSC2 or LKB1 result in similar cancer symptoms with a common clinical manifestation. Therefore, this signal pathway that ensures that cells proliferate under environmentally appropriate conditions can be used by cancer cells to survive and grow under conditions of lack of nutrients. In the process of screening for kinase inhibitors, a series of drugs targeting kinases such as mTOR, PI (3)K, RTKs and Raf have been designed. In the molecular mechanism of cancer research, although this signaling pathway is the most thoroughly studied, the physiological functions of these kinases in cells and organisms are far more complicated than we think.

4.Wnt signal

The Wnt signaling pathway is widely distributed in invertebrates and vertebrates and is a highly conserved signaling pathway during species evolution. Wnt signaling plays a crucial role in the early development of animal embryos, organ formation, tissue regeneration and other physiological processes. If a key protein in this signaling pathway is mutated, resulting in abnormal activation of the signal, it may induce cancer. In 1982, R. Nusse and H.E. Varmus cloned the first Wnt gene in mouse breast cancer cells, initially named Int1 (integration 1). Later studies found that the mouse Int gene and the wingless gene wg (wingless) of Drosophila are homologous genes, and thus the two are collectively referred to as Wnt. H.E. Varmus I also won the 1989 Nobel Prize in Physiology and Medicine for his outstanding contribution to cancer research.

Wnt is a type of secreted glycoprotein that acts through autocrine or paracrine. The main components of the Wnt signaling pathway include: the secreted protein Wnt family, the transmembrane receptor Frizzled family, CK1, Deskerled, GSK3, APC, Axin, β-Catenin, and the transcription factor TCF/LEF family. The Wnt signaling pathway is a complex regulatory network that is currently thought to include three branches: the canonical Wnt signaling pathway, which activates gene transcription via β-Catenin; the Wnt/PCP pathway (planner cell polarity pathway), which activates JNK via small G proteins (c -Jun N-terminal kinase) regulates cytoskeletal rearrangement; the Wnt/Ca2+ pathway affects cell adhesion and related gene expression by releasing intracellular Ca2+. It is generally mentioned that the Wnt signaling pathway mainly refers to the classical Wnt signaling pathway mediated by β-Catenin.

5. BMP signaling pathway

BMP (bone morphogenetic protein) is an important member of the TGF-β (transforming growth factor-β) superfamily [6]. By regulating the activity of a range of downstream genes, many important biological processes such as mesoderm formation, nervous system differentiation, tooth and bone development, and cancer development are controlled. The BMP signal is specifically transmitted by the ligand BMP to specifically bind to the serine/threonine kinase receptor (BMPR) on the cell membrane to form a ligand receptor binary complex. At the same time, the type II receptor (BMPR2) is able to activate the type I receptor (BMPR1) and further transmit signals to the Smad molecules in the cell. The Smad protein plays a key role in the transmission of BMP and TGF-β signals from the cell membrane to the nucleus. Activated type I receptor (BMPR1) further phosphorylates Smad proteins (Smad1, Smad5, and Smad8), causing Smad molecules to detach from cell membrane receptors and bind to Smad4 molecules (common Smad, Co-Smad) in the cytoplasm Enter the nucleus. In the nucleus, the Smad multi-component complex acts on a specific target gene with the participation of other DNA-binding proteins to regulate the transcription of the target gene.

6. Ras2MAPK signal transduction pathway

1) Ras upstream channel

Ras can be activated by complex networks. First, phosphorylation-activated receptors, such as PDGFR, EGFR directly bind to growth factor receptor binding protein (Grb2), which also bind indirectly and phosphorylate proteins containing the src homology region 2 (SH2) domain (For example, Shc, Syp), then activate Grb2. In addition, the src homology 3 (SH3) domain of Grb2 binds to target proteins such as mSos1, mSos2, C3G and dynamin. The SH3 structure of C3G and connexin Crk Domain binding after coupling tyrosine phosphorylation to activate Ras. Crk can also bind mSos1 to activate Ras.Grb2 to bind to activated receptors to promote the localization of guanylate exchange factor (Sos) protein on the cell membrane adjacent to Ras. Sos forms a complex with Ras. After GTP replaces GDP and Ras, Ras is activated. When GTP is hydrolyzed into GDP, Ras is inactivated. Ras has intrinsic GTPase activity, and its activity can be regulated by RasGAPs, thus RasGAPs act as Ras activity regulation. The role of the agent. In addition, Ras inactivation is also highly regulated. Currently, there are three proteins that can hydrolyze GTP to inactivate Ras, which are P120GAP, neurofibromin and GAP1m, collectively referred to as RasGAPs.

2) Ras downstream path

At present, the Ras/Raf pathway is the clearest signal transduction pathway. When GTP replaces GDP and Ras binds, Ras is activated, then activates the silrethine kinase cascade amplification effect, recruiting intracellular Raf1 serine kinase to the cell membrane, Raf kinase phosphorylates MAPK kinase (MAPKK), and MAPKK activates MAPK. MAPK is activated and then transferred to the nucleus to directly activate transcription factors. In addition, MAPK stimulates Fos, Jun transcription factor forms transcription factor AP1, which is related to the specific DNA sequence next to the myc gene binds to initiate transcription. The myc gene product is also a transcription factor that activates other genes. Ultimately, these signals are concentrated to induce the expression and activity of D-type Cyclin. D-type Cyclin and Cyclin-dependent kinases (such as CDK4 and CDK6) form a complex that forms the cell from the G1 phase to the S phase. Therefore, the Ras/Raf pathway plays a key role between the receptor signal and G1 phase progression, however, Ras/Raf Pathway is not the only pathway regulating G1 progression. Ras and Raf alone do not promote Raf kinase activity, while Raf can be activated by Ras-independent mechanisms (eg, activated by Src tyrosine kinase and PKC), MAPK Can be independent of Ra the s mechanism (eg, by modulating the activity of integrins) is activated. This indicates that each signaling protein in the cascade reaction can be activated by multiple upstream proteins, and they may have additional target proteins.

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