Misplaced Pages

#195804

60-599: 1A15 , 1QG7 , 1SDF , 1VMC , 2J7Z , 2K01 , 2K03 , 2K04 , 2K05 , 2KEC , 2KED , 2KEE , 2KOL , 2NWG , 2SDF , 3GV3 , 3HP3 , 4LMQ , 4UAI , 2N55 6387 20315 ENSG00000107562 ENSMUSG00000061353 P48061 P40224 NM_199168 NM_000609 NM_001033886 NM_001178134 NM_001277990 NM_001012477 NM_013655 NM_021704 NP_000600 NP_001029058 NP_001171605 NP_001264919 NP_954637 NP_001012495 NP_038683 NP_068350 The stromal cell-derived factor 1 ( SDF-1 ), also known as C-X-C motif chemokine 12 (CXCL12),

120-403: A 3 10 -helix , three β-strands and a C-terminal α-helix . These helices and strands are connected by turns called 30s , 40s and 50s loops; the third and fourth cysteines are located in the 30s and 50s loops. Members of the chemokine family are divided into four groups depending on the spacing of their first two cysteine residues. Thus the nomenclature for chemokines is, e.g.: CCL1 for

180-414: A molecular mass of between 8 and 10 kDa . They are approximately 20-50% identical to each other; that is, they share gene sequence and amino acid sequence homology. They all also possess conserved amino acids that are important for creating their 3-dimensional or tertiary structure , such as (in most cases) four cysteines that interact with each other in pairs to create a Greek key shape that

240-443: A chemoattractant for neutrophils. In contrast to the homeostatic chemokine receptors, there is significant promiscuity (redundancy) associated with binding receptor and inflammatory chemokines. This often complicates research on receptor-specific therapeutics in this area. Proteins are classified into the chemokine family based on their structural characteristics, not just their ability to attract cells. All chemokines are small, with

300-462: A community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). A neurological condition that results from a faulty interaction between the immune and nervous systems in multiple sclerosis . MS is characterized by demyelination of nerves due to

360-596: A conserved cysteine residue that allow formation of a disulfide bridge between these loops. G proteins are coupled to the C-terminal end of the chemokine receptor to allow intracellular signaling after receptor activation, while the N-terminal domain of the chemokine receptor determines ligand binding specificity. Chemokine receptors associate with G-proteins to transmit cell signals following ligand binding. Activation of G proteins, by chemokine receptors, causes

420-837: A family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers. Cytokine proteins are classified as chemokines according to behavior and structural characteristics. In addition to being known for mediating chemotaxis, chemokines are all approximately 8–10 kilodaltons in mass and have four cysteine residues in conserved locations that are key to forming their 3-dimensional shape. These proteins have historically been known under several other names including

480-434: A gene that serves as an initial binding site—resulting in slightly modified transcripts and protein isoforms. Generally, one protein isoform is labeled as the canonical sequence based on criteria such as its prevalence and similarity to orthologous —or functionally analogous—sequences in other species. Isoforms are assumed to have similar functional properties, as most have similar sequences, and share some to most exons with

540-524: A positive role for these molecules in controlling the natural course of HIV infection. Isoforms A protein isoform , or " protein variant ", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have unique functions. A set of protein isoforms may be formed from alternative splicings , variable promoter usage, or other post-transcriptional modifications of

600-461: A role in cerebellar formation through the migration of neurons. Within the CNS, CXCL12 contributes to cell proliferation, neurogenesis (nervous tissue development and growth), as well as neuroinflammation. Neural progenitor cells (NPCs) are stem cells that differentiate into glial and neuronal cells. CXCL12 promotes their migration to lesion sites within the brain, specifically over extensive ranges. Once at

660-411: A single gene; post-translational modifications are generally not considered. (For that, see Proteoforms .) Through RNA splicing mechanisms, mRNA has the ability to select different protein-coding segments ( exons ) of a gene, or even different parts of exons from RNA to form different mRNA sequences. Each unique sequence produces a specific form of a protein. The discovery of isoforms could explain

SECTION 10

#1732765982196

720-545: A small number of CC chemokines possess six cysteines (C6-CC chemokines). C6-CC chemokines include CCL1, CCL15, CCL21, CCL23 and CCL28. CC chemokines induce the migration of monocytes and other cell types such as NK cells and dendritic cells . Examples of CC chemokine include monocyte chemoattractant protein-1 (MCP-1 or CCL2) which induces monocytes to leave the bloodstream and enter the surrounding tissue to become tissue macrophages . CCL5 (or RANTES ) attracts cells such as T cells, eosinophils and basophils that express

780-448: A specific amino acid sequence (or motif) of glutamic acid - leucine - arginine (or ELR for short) immediately before the first cysteine of the CXC motif (ELR-positive), and those without an ELR motif (ELR-negative). ELR-positive CXC chemokines specifically induce the migration of neutrophils , and interact with chemokine receptors CXCR1 and CXCR2 . An example of an ELR-positive CXC chemokine

840-411: A suppression of that mislocalization. Additionally, this pretreatment with CXCL decreased the prevalence of apoptosis and oxidative damage normally caused by the presence of the beta-amyloid plaque. Chemokines and chemokine receptors, of which CXCR stands out, regulate multiple processes such as morphogenesis, angiogenesis, and immune responses and are considered potential targets for drug development. It

900-408: A wide variety of cells in response to bacterial infection, viruses and agents that cause physical damage such as silica or the urate crystals that occur in gout . Their release is often stimulated by pro-inflammatory cytokines such as interleukin 1 . Inflammatory chemokines function mainly as chemoattractants for leukocytes , recruiting monocytes , neutrophils and other effector cells from

960-472: Is interleukin-8 (IL-8), which induces neutrophils to leave the bloodstream and enter into the surrounding tissue. Other CXC chemokines that lack the ELR motif, such as CXCL13 , tend to be chemoattractant for lymphocytes. CXC chemokines bind to CXC chemokine receptors , of which seven have been discovered to date, designated CXCR1-7. The third group of chemokines is known as the C chemokines (or γ chemokines), and

1020-486: Is a chemokine protein that in humans is encoded by the CXCL12 gene on chromosome 10 . It is ubiquitously expressed in many tissues and cell types. Stromal cell-derived factors 1-alpha and 1-beta are small cytokines that belong to the chemokine family, members of which activate leukocytes and are often induced by proinflammatory stimuli such as lipopolysaccharide , TNF , or IL1 . The chemokines are characterized by

1080-410: Is a characteristic of chemokines. Intramolecular disulfide bonds typically join the first to third, and the second to fourth cysteine residues, numbered as they appear in the protein sequence of the chemokine. Typical chemokine proteins are produced as pro-peptides , beginning with a signal peptide of approximately 20 amino acids that gets cleaved from the active (mature) portion of the molecule during

1140-592: Is a major molecular mechanism that may contribute to protein diversity. The spliceosome , a large ribonucleoprotein , is the molecular machine inside the nucleus responsible for RNA cleavage and ligation , removing non-protein coding segments ( introns ). Because splicing is a process that occurs between transcription and translation , its primary effects have mainly been studied through genomics techniques—for example, microarray analyses and RNA sequencing have been used to identify alternatively spliced transcripts and measure their abundances. Transcript abundance

1200-464: Is called fractalkine (or CX 3 CL1). It is both secreted and tethered to the surface of the cell that expresses it, thereby serving as both a chemoattractant and as an adhesion molecule . Chemokine receptors are G protein-coupled receptors containing 7 transmembrane domains that are found on the surface of leukocytes . Approximately 19 different chemokine receptors have been characterized to date, which are divided into four families depending on

1260-422: Is derived by the protein's structure/function, as well as the cell type and developmental stage during which they are produced. Determining specificity becomes more complicated when a protein has multiple subunits and each subunit has multiple isoforms. For example, the 5' AMP-activated protein kinase (AMPK), an enzyme, which performs different roles in human cells, has 3 subunits: In human skeletal muscle,

SECTION 20

#1732765982196

1320-400: Is expressed in many tissues in mice including brain , thymus , heart , lung , liver , kidney , spleen , platelets and bone marrow . CXCL12 is strongly chemotactic for lymphocytes . During embryogenesis, it directs the migration of hematopoietic cells from fetal liver to bone marrow and the formation of large blood vessels. It has also been shown that CXCL12 signalling regulates

1380-470: Is indicated by clinical samples that a high expression level of CXCR4 in idiopathic pulmonary fibrosis lungs. Experimental evidence further indicate that CXCR4/CXCR12 is associated with the pathogenesis of lung fibrosis. In the gastrointestinal tract system, the CXCL12-CXCR4 axis is under investigation as an anti-fibrotic therapy in the treatment for chronic pancreatitis. For instance, blocking CXCR4 ,

1440-532: Is no conclusive evidence that it acts primarily by producing novel protein isoforms. Alternative splicing generally describes a tightly regulated process in which alternative transcripts are intentionally generated by the splicing machinery. However, such transcripts are also produced by splicing errors in a process called "noisy splicing," and are also potentially translated into protein isoforms. Although ~95% of multi-exonic genes are thought to be alternatively spliced, one study on noisy splicing observed that most of

1500-543: Is often used as a proxy for the abundance of protein isoforms, though proteomics experiments using gel electrophoresis and mass spectrometry have demonstrated that the correlation between transcript and protein counts is often low, and that one protein isoform is usually dominant. One 2015 study states that the cause of this discrepancy likely occurs after translation, though the mechanism is essentially unknown. Consequently, although alternative splicing has been implicated as an important link between variation and disease, there

1560-487: Is possible routing antigen-presenting cells (APC) to lymph nodes during the adaptive immune response. Among other homeostatic chemokine receptors include: CCR9, CCR10, and CXCR5, which are important as part of the cell addresses for tissue-specific homing of leukocytes . CCR9 supports the migration of leukocytes into the intestine , CCR10 to the skin and CXCR5 supports the migration of B-cell to follicles of lymph nodes . As well CXCL12 (SDF-1) constitutively produced in

1620-459: Is the receptor for CXCL12. This CXCL12-CXCR4 interaction used to be considered exclusive (unlike for other chemokines and their receptors), but recently, it was suggested that CXCL12 may also bind the CXCR7 receptor (now called ACKR3). By blocking CXCR4, a major coreceptor for HIV-1 entry, CXCL12 acts as an endogenous inhibitor of CXCR4-tropic HIV-1 strains. During embryonic development, CXCL12 plays

1680-441: Is unlike all other chemokines in that it has only two cysteines; one N-terminal cysteine and one cysteine downstream. Two chemokines have been described for this subgroup and are called XCL1 ( lymphotactin -α) and XCL2 ( lymphotactin -β). A fourth group has also been discovered and members have three amino acids between the two cysteines and is termed CX 3 C chemokine (or d-chemokines). The only CX 3 C chemokine discovered to date

1740-464: The MAP kinase pathway ) that generate responses like chemotaxis , degranulation , release of superoxide anions and changes in the avidity of cell adhesion molecules called integrins within the cell harbouring the chemokine receptor. The discovery that the β chemokines RANTES , MIP ( macrophage inflammatory proteins ) 1α and 1β (now known as CCL5, CCL3 and CCL4 respectively) suppress HIV -1 provided

1800-897: The SIS family of cytokines , SIG family of cytokines , SCY family of cytokines , Platelet factor-4 superfamily or intercrines . Some chemokines are considered pro- inflammatory and can be induced during an immune response to recruit cells of the immune system to a site of infection , while others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development . Chemokines are found in all vertebrates , some viruses and some bacteria , but none have been found in other invertebrates . Chemokines have been classified into four main subfamilies: CXC, CC, CX3C and C. All of these proteins exert their biological effects by interacting with G protein -linked transmembrane receptors called chemokine receptors , that are selectively found on

1860-439: The blood to sites of infection or tissue damage. Certain inflammatory chemokines activate cells to initiate an immune response or promote wound healing . They are released by many different cell types and serve to guide cells of both innate immune system and adaptive immune system . Chemokines are functionally divided into two groups: The main function of chemokines is to manage the migration of leukocytes ( homing ) in

Stromal cell-derived factor 1 - Misplaced Pages Continue

1920-421: The bone marrow promotes proliferation of progenitor B cells in the bone marrow microenvironment. Inflammatory : inflammatory chemokines are produced in high concentrations during infection or injury and determine the migration of inflammatory leukocytes into the damaged area. Typical inflammatory chemokines include: CCL2, CCL3 and CCL5 , CXCL1, CXCL2 and CXCL8 . A typical example is CXCL-8, which acts as

1980-508: The A2B adenosine receptor followed by stimulation of fibroblast growth factor and increased expression of CXCL12. A multi-locus genetic risk score study based on a combination of 27 loci, including the CXCL12 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on

2040-425: The abundance of mRNA transcript isoforms does not necessarily correlate with the abundance of protein isoforms. Three-dimensional protein structure comparisons can be used to help determine which, if any, isoforms represent functional protein products, and the structure of most isoforms in the human proteome has been predicted by AlphaFold and publicly released at isoform.io . The specificity of translated isoforms

2100-428: The band 10q11.21 and contains 4 exons. . This gene produces 7 isoforms through alternative splicing . This protein belongs to the intercrine alpha ( chemokine CXC) family. SDF-1 is produced in two forms, SDF-1α/CXCL12a and SDF-1β/CXCL12b, by alternate splicing of the same gene. Chemokines are characterized by the presence of four conserved cysteines , which form two disulfide bonds . The CXCL12 proteins belong to

2160-411: The blood brain barrier. however, excessive production and accumulation of CXCL12 can become toxic and the inflammation produced may result in serious consequences. In humans, CXCL12 has been implicated in a wide variety of biomedical conditions involving several organ systems. Furthermore, CXCL12 signaling in conjunction with CXCR7 signaling has been implicated in the progression of pancreatic cancer. In

2220-427: The body's immune system attacking the CNS. Elevated levels of CXCL12 are observed in the cerebral spinal fluid of patients with MS. CXCL12 crosses the blood–brain barrier and causes neuroinflammation that contributes to axonal damage and therefore the progression of multiple sclerosis. Though CXCL12 may be detrimental for those with MS, recent research is suggesting that this chemokine may be beneficial in decreasing

2280-491: The canonical sequence. However, some isoforms show much greater divergence (for example, through trans-splicing ), and can share few to no exons with the canonical sequence. In addition, they can have different biological effects—for example, in an extreme case, the function of one isoform can promote cell survival, while another promotes cell death—or can have similar basic functions but differ in their sub-cellular localization. A 2016 study, however, functionally characterized all

2340-486: The different low-abundance transcripts are noise, and predicts that most alternative transcript and protein isoforms present in a cell are not functionally relevant. Other transcriptional and post-transcriptional regulatory steps can also produce different protein isoforms. Variable promoter usage occurs when the transcriptional machinery of a cell ( RNA polymerase , transcription factors , and other enzymes ) begin transcription at different promoters—the region of DNA near

2400-573: The discrepancy between the small number of protein coding regions of genes revealed by the human genome project and the large diversity of proteins seen in an organism: different proteins encoded by the same gene could increase the diversity of the proteome . Isoforms at the RNA level are readily characterized by cDNA transcript studies. Many human genes possess confirmed alternative splicing isoforms. It has been estimated that ~100,000 expressed sequence tags ( ESTs ) can be identified in humans. Isoforms at

2460-439: The expression of CD20 on B cells. CXCL12 is also chemotactic for mesenchymal stem cells and is expressed in the area of inflammatory bone destruction, where it mediates their suppressive effect on osteoclastogenesis . In adulthood, CXCL12 plays an important role in angiogenesis by recruiting endothelial progenitor cells (EPCs) from the bone marrow through a CXCR4 dependent mechanism. CXCR4 , previously called LESTR or fusin,

Stromal cell-derived factor 1 - Misplaced Pages Continue

2520-464: The function of each isoform must generally be determined separately, most identified and predicted isoforms still have unknown functions. A glycoform is an isoform of a protein that differs only with respect to the number or type of attached glycan . Glycoproteins often consist of a number of different glycoforms, with alterations in the attached saccharide or oligosaccharide . These modifications may result from differences in biosynthesis during

2580-532: The group of CXC chemokines, whose initial pair of cysteines are separated by one intervening amino acid . In addition, the first 8 residues of the CXCL12 N-terminal serve as a receptor binding site, though only Lys-1 and Pro-2 directly participated in activating the receptor. Meanwhile, the RFFESH motif (residues 12-17) in the loop region function as a docking site for CXCL12 receptor binding. CXCL12

2640-482: The initial connection and indicated that these molecules might control infection as part of immune responses in vivo, and that sustained delivery of such inhibitors have the capacity of long-term infection control. The association of chemokine production with antigen-induced proliferative responses, more favorable clinical status in HIV infection, as well as with an uninfected status in subjects at risk for infection suggests

2700-413: The isoforms of 1,492 genes and determined that most isoforms behave as "functional alloforms." The authors came to the conclusion that isoforms behave like distinct proteins after observing that the functional of most isoforms did not overlap. Because the study was conducted on cells in vitro , it is not known if the isoforms in the expressed human proteome share these characteristics. Additionally, because

2760-506: The ligand 1 of the CC-family of chemokines, and CCR1 for its respective receptor. The CC chemokine (or β-chemokine ) proteins have two adjacent cysteines ( amino acids ), near their amino terminus . There have been at least 27 distinct members of this subgroup reported for mammals, called CC chemokine ligands ( CCL )-1 to -28; CCL10 is the same as CCL9 . Chemokines of this subfamily usually contain four cysteines (C4-CC chemokines), but

2820-456: The preferred form is α2β2γ1. But in the human liver, the most abundant form is α1β2γ1. The primary mechanisms that produce protein isoforms are alternative splicing and variable promoter usage, though modifications due to genetic changes, such as mutations and polymorphisms are sometimes also considered distinct isoforms. Alternative splicing is the main post-transcriptional modification process that produces mRNA transcript isoforms, and

2880-613: The presence of 4 conserved cysteines that form 2 disulfide bonds . They can be classified into 2 subfamilies. In the CC subfamily , the cysteine residues are adjacent to each other. In the CXC subfamily , they are separated by an intervening amino acid. The SDF1 proteins belong to the latter group. CXCL12 signaling has been observed in several cancers. The CXCL12 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease . The CXCL12 gene resides on chromosome 10 at

2940-404: The process of glycosylation , or due to the action of glycosidases or glycosyltransferases . Glycoforms may be detected through detailed chemical analysis of separated glycoforms, but more conveniently detected through differential reaction with lectins , as in lectin affinity chromatography and lectin affinity electrophoresis . Typical examples of glycoproteins consisting of glycoforms are

3000-592: The process of its secretion from the cell. The first two cysteines, in a chemokine, are situated close together near the N-terminal end of the mature protein, with the third cysteine residing in the centre of the molecule and the fourth close to the C-terminal end . A loop of approximately ten amino acids follows the first two cysteines and is known as the N-loop . This is followed by a single-turn helix, called

3060-603: The progression of patients with Alzheimer's. Alzheimer's is another neurological condition and the most common form of dementia where cognition significantly declines. One main characteristic of Alzheimer's is the accumulation of a brain plaque known as beta-amyloid. There are neuroprotective aspects of CXCL12 in mice with these plaques/Alzheimer's. PAK is a protein associated with maintaining dendritic spines, which are essential at synapses in receiving information from axons. Mislocalization of PAK occurs in patients with Alzheimer's, however pretreatment of neurons in mice with CXCL12 showed

SECTION 50

#1732765982196

3120-407: The protein level can manifest in the deletion of whole domains or shorter loops, usually located on the surface of the protein. One single gene has the ability to produce multiple proteins that differ both in structure and composition; this process is regulated by the alternative splicing of mRNA, though it is not clear to what extent such a process affects the diversity of the human proteome, as

3180-399: The receptor CCR5 . Increased CCL11 levels in blood plasma are associated with aging (and reduced neurogenesis ) in mice and humans. The two N-terminal cysteines of CXC chemokines (or α-chemokines ) are separated by one amino acid, represented in this name with an "X". There have been 17 different CXC chemokines described in mammals, that are subdivided into two categories, those with

3240-575: The receptor for CXCL12, with Plerixafor (AMD-3100) increased the effectiveness of combretastatin in a mouse model of breast cancer, presumably by preventing macrophages from being recruited to tumours. [15] [16] AMD-3100 is also widely used in combination with G-CSF for mobilizing hematopoietic stem cells into the blood stream, allowing collection for bone marrow transplant . Chemokine Chemokines (from Ancient Greek χῠμείᾱ (khumeíā)  'alchemy' and κῑ́νησῐς (kī́nēsis)  'movement'), or chemotactic cytokines, are

3300-442: The respective anatomical locations in inflammatory and homeostatic processes. Basal : homeostatic chemokines are basal produced in the thymus and lymphoid tissues. Their homeostatic function in homing is best exemplified by the chemokines CCL19 and CCL21 (expressed within lymph nodes and on lymphatic endothelial cells) and their receptor CCR7 (expressed on cells destined for homing in cells to these organs). Using these ligands

3360-421: The site of damage, NPCs may begin stem cell based tissue repair to the lesion. The CXCL12/CXCR4 axis provides guidance cues for axons and neurites hence promoting neurite outgrowth (neurons forming projections) and neurogenesis. Like other chemokines, CXCL12 is involved with cell migration that contributes to inflammation. In regards to the CNS, CXCL12 plays a role in neuroinflammation by attracting leukocytes across

3420-487: The subsequent activation of an enzyme known as phospholipase C (PLC). PLC cleaves a molecule called phosphatidylinositol (4,5)-bisphosphate (PIP2) into two second messenger molecules known as Inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores. These events promote many signaling cascades (such as

3480-910: The surfaces of their target cells. The major role of chemokines is to act as a chemoattractant to guide the migration of cells. Cells that are attracted by chemokines follow a signal of increasing chemokine concentration towards the source of the chemokine. Some chemokines control cells of the immune system during processes of immune surveillance, such as directing lymphocytes to the lymph nodes so they can screen for invasion of pathogens by interacting with antigen-presenting cells residing in these tissues. These are known as homeostatic chemokines and are produced and secreted without any need to stimulate their source cells. Some chemokines have roles in development; they promote angiogenesis (the growth of new blood vessels ), or guide cells to tissues that provide specific signals critical for cellular maturation. Other chemokines are inflammatory and are released from

3540-631: The type of chemokine they bind; CXCR that bind CXC chemokines, CCR that bind CC chemokines, CX3CR1 that binds the sole CX3C chemokine (CX3CL1), and XCR1 that binds the two XC chemokines (XCL1 and XCL2). They share many structural features; they are similar in size (with about 350 amino acids ), have a short, acidic N-terminal end, seven helical transmembrane domains with three intracellular and three extracellular hydrophilic loops, and an intracellular C-terminus containing serine and threonine residues important for receptor regulation. The first two extracellular loops of chemokine receptors each has

3600-408: The urinary tract system, methylation of the CXCL12 promoter and expression of PD-L1 may be powerful prognostic biomarkers for biochemical recurrence in prostate carcinoma patients after radical prostatectomy, and further studies are ongoing to confirm if CXCL12 methylation may aid in active surveillance strategies. In the field of oncology, melanoma associated fibroblasts are stimulated by stimulation of

#195804