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51-396: 6093 19877 ENSG00000067900 ENSMUSG00000024290 Q13464 P70335 NM_005406 NM_009071 NP_005397 NP_033097 ROCK1 is a protein serine/threonine kinase also known as rho-associated, coiled-coil-containing protein kinase 1 . Other common names are ROKβ and P160ROCK. ROCK1 is a major downstream effector of the small GTPase RhoA and is a regulator of

102-404: A ceramide. This composition allows sphingomyelin to play significant roles in signaling pathways: the degradation and synthesis of sphingomyelin produce important second messengers for signal transduction. Sphingomyelin obtained from natural sources, such as eggs or bovine brain, contains fatty acids of various chain length. Sphingomyelin with set chain length, such as palmitoylsphingomyelin with

153-447: A crucial role in tumor cell migration and metastasis. This activated ROCK1 also activates LIM kinase , which, phosphorylates cofilin , inhibiting its actin-depolymerizing activity. This depolymerization results in stabilization of actin filaments and decreased branching which promotes contraction. Cardiac troponin is another ROCK1 substrate that upon phosphorylation causes reduction in tension in cardiac myocytes . ROCK1 also acts as

204-503: A deficiency in the lysosomal enzyme acid sphingomyelinase , which causes the accumulation of sphingomyelin in spleen , liver , lungs , bone marrow , and brain , causing irreversible neurological damage. Of the two types involving sphingomyelinase , type A occurs in infants. It is characterized by jaundice , an enlarged liver, and profound brain damage. Children with this type rarely live beyond 18 months. Type B involves an enlarged liver and spleen, which usually occurs in

255-405: A medium effect size for negative and total symptoms of schizophrenia. There also is evidence that L ‐serine could acquire a therapeutic role in diabetes. D -Serine is being studied in rodents as a potential treatment for schizophrenia. D -Serine also has been described as a potential biomarker for early Alzheimer's disease (AD) diagnosis, due to a relatively high concentration of it in

306-414: A neuromodulator by coactivating NMDA receptors , making them able to open if they then also bind glutamate . D -serine is a potent agonist at the glycine site (NR1) of canonical diheteromeric NMDA receptors . For the receptor to open, glutamate and either glycine or D -serine must bind to it; in addition a pore blocker must not be bound (e.g. Mg or Zn ). Some research has shown that D -serine

357-471: A non-essential amino acid has come to be considered as conditional, since vertebrates such as humans cannot always synthesize optimal quantities over entire lifespans. Safety of L -serine has been demonstrated in an FDA-approved human phase I clinical trial with Amyotrophic Lateral Sclerosis, ALS , patients (ClinicalTrials.gov identifier: NCT01835782), but treatment of ALS symptoms has yet to be shown. A 2011 meta-analysis found adjunctive sarcosine to have

408-446: A patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD). Besides disruption of serine biosynthesis, its transport may also become disrupted. One example is spastic tetraplegia, thin corpus callosum, and progressive microcephaly , a disease caused by mutations that affect the function of the neutral amino acid transporter A . The classification of L -serine as

459-420: A saturated 16 acyl chain, is available commercially. Ideally, sphingomyelin molecules are shaped like a cylinder, however many molecules of sphingomyelin have a significant chain mismatch (the lengths of the two hydrophobic chains are significantly different). The hydrophobic chains of sphingomyelin tend to be much more saturated than other phospholipids. The main transition phase temperature of sphingomyelins

510-439: A significant role in the phase of sphingomyelin. Sphingomyelin are also more prone to intermolecular hydrogen bonding than other phospholipids. Sphingomyelin is synthesized at the endoplasmic reticulum (ER), where it can be found in low amounts, and at the trans Golgi. It is enriched at the plasma membrane with a greater concentration on the outer than the inner leaflet. The Golgi complex represents an intermediate between

561-842: A suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. ROCK1 has a diverse range of functions in the body. It is a key regulator of actin-myosin contraction, stability, and cell polarity . These contribute to many progresses such as regulation of morphology, gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation. Other functions involve smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility. These functions are activated by phosphorylation of DAPK3 , GFAP , LIMK1 , LIMK2 , MYL9/MLC2 , PFN1 and PPP1R12A . Additionally, ROCK1 phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing . It

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612-417: A variable degree to treatment with L -serine, sometimes combined with glycine. Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, as well as for evaluating diagnostic and therapeutic strategies

663-522: A very faint musty aroma. D -Serine is sweet with an additional minor sour taste at medium and high concentrations. Serine deficiency disorders are rare defects in the biosynthesis of the amino acid L -serine. At present three disorders have been reported: These enzyme defects lead to severe neurological symptoms such as congenital microcephaly and severe psychomotor retardation and in addition, in patients with 3-phosphoglycerate dehydrogenase deficiency to intractable seizures. These symptoms respond to

714-409: Is a lipid-soluble second messenger that can pass along a signal cascade. In addition, the degradation of sphingomyelin can produce ceramide which is involved in the apoptotic signaling pathway. Sphingomyelin has been found to have a role in cell apoptosis by hydrolyzing into ceramide . Studies in the late 1990s had found that ceramide was produced in a variety of conditions leading to apoptosis. It

765-518: Is a more potent agonist at the NMDAR glycine site than glycine itself. However, D-serine has been shown to work as an antagonist/inverse co-agonist of t -NMDA receptors through the glycine binding site on the GluN3 subunit. D -serine was thought to exist only in bacteria until relatively recently; it was the second D amino acid discovered to naturally exist in humans, present as a signaling molecule in

816-501: Is a serine/threonine kinase with molecular weight of 158 kDa. It is a homodimer composed of a catalytic kinase domain (residues76-338) located at the amino or N-terminus of the protein, a coiled-coil region (residues 425-1100) containing the Rho-binding domain , and a pleckstrin-homology domain (residues 1118-1317) with a cysteine-rich domain. When a substrate is absent, ROCK1 is an autoinhibited loop structure. Enzyme activity of ROCK1

867-462: Is a type of sphingolipid found in animal cell membranes , especially in the membranous myelin sheath that surrounds some nerve cell axons . It usually consists of phosphocholine and ceramide , or a phosphoethanolamine head group; therefore, sphingomyelins can also be classified as sphingophospholipids. In humans, SPH represents ~85% of all sphingolipids, and typically make up 10–20 mol % of plasma membrane lipids. Sphingomyelin

918-482: Is also higher compared to the phase transition temperature of similar phospholipids, near 37 °C. This can introduce lateral heterogeneity in the membrane, generating domains in the membrane bilayer. Sphingomyelin undergoes significant interactions with cholesterol. Cholesterol has the ability to eliminate the liquid to solid phase transition in phospholipids. Due to sphingomyelin transition temperature being within physiological temperature ranges, cholesterol can play

969-560: Is also required for centrosome positioning and centrosome-dependent exit from mitosis. ROCK1 has been shown to interact with: In humans, the main function of ROCK1 is actomyosin contractility. As mentioned before, this contributes to many proximal progresses such as regulation of morphology, motility, and cell–cell and cell–matrix adhesion. In addition, ROCK kinases influence more distal cellular processes including gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation. Given this diverse range of functions, it

1020-399: Is an α- amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − NH 3 form under biological conditions), a carboxyl group (which is in the deprotonated − COO form under biological conditions), and a side chain consisting of a hydroxymethyl group, classifying it as a polar amino acid. It can be synthesized in

1071-440: Is hydrolyzed to serine by phosphoserine phosphatase ( EC 3.1.3.3 ). In bacteria such as E. coli these enzymes are encoded by the genes serA (EC 1.1.1.95), serC (EC 2.6.1.52), and serB (EC 3.1.3.3). Serine hydroxymethyltransferase (SMHT) also catalyzes the biosynthesis of glycine (retro-aldol cleavage) from serine, transferring the resulting formalddehyde synthon to 5,6,7,8-tetrahydrofolate . However, that reaction

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1122-703: Is inhibited when the pleckstrin-homology and Rho-binding domains in the C-terminus independently bind to the N-terminus kinase domain. When a substrate such as GTP-bound RhoA binds to the Rho-binding region of the coiled-coil domain, the interactions between the N-terminus and the C-terminus are disrupted, thus activating the protein. Cleavage of the C-terminal inhibitory domain by caspase-3 during apoptosis can also activate

1173-529: Is involved in a pathway for smooth muscle contraction. When ROCK1 is activated by binding of GTPase RhoA it produces multiple signaling cascades. For example, RhoA is one of the downstream signaling cascades activated by vascular endothelial growth factor ( VEGF ). ROCK1 acts as a negative regulator of VEGF endothelial cell activation and angiogenesis. ROCK1 activation by RhoA also promotes stabilization of F-actin , phosphorylation of regulatory myosin light chain (MLC) and an increase in contractility, which plays

1224-495: Is not surprising that ROCK1 has been implicated in numerous aspects of cancer. Recent studies have explored the role of ROCK1 in cancer with particular attention focused on cell motility, metastasis, and angiogenesis. Rho GTPases such as RhoA are highly involved in morphologic changes in cells. When a tumor progresses from invasive to metastatic form it requires that they undergo these dramatic morphologic changes. Therefore, increased expression of RhoA and its downstream effector ROCK1

1275-408: Is often observed in human cancers. These cancers are typically more invasive and metastatic phenotypes. Increased expression of RhoA and ROCK1 in endothelial cell migration pathways can cause an increase in angiogenesis and metastatic behavior in tumor cells. It has been suggested that ROCK1 either regulates the expression of angiogenic factors or ROCK1 activation facilitates angiogenesis by increasing

1326-580: Is one other isoform of ROCK known as ROCK2. ROCK2 is located at 2p24 and is highly homologous with ROCK1 with an overall amino acid sequence identity of 65%. The identity in the Rho-binding domain is 58% and approximately 92% in the kinase domain. The ROCK isoforms are encoded by two different identified genes and are ubiquitously expressed. GTPase-RhoA binding can increase the activity of ROCK1 by 1.5-2-fold. Without RhoA binding, lipids such as arachidonic acid or sphingosine phosphorylcholine can increase ROCK1 activity 5- to 6-fold. These two lipids interact with

1377-502: Is particularly rich in sphingomyelin, suggesting its role as an insulator of nerve fibers. The plasma membrane of other cells is also abundant in sphingomyelin, though it is largely to be found in the exoplasmic leaflet of the cell membrane. There is, however, some evidence that there may also be a sphingomyelin pool in the inner leaflet of the membrane. Moreover, neutral sphingomyelinase-2 – an enzyme that breaks down sphingomyelin into ceramide – has been found to localise exclusively to

1428-465: Is produced as a byproduct when the phosphocholine is transferred. Sphingomyelin breakdown is responsible for initiating many universal signaling pathways. It is hydrolyzed by sphingomyelinases (sphingomyelin specific type-C phospholipases). The phosphocholine head group is released into the aqueous environment while the ceramide diffuses through the membrane. The membranous myelin sheath that surrounds and electrically insulates many nerve cell axons

1479-475: Is reduced, yielding dihydrosphingosine. The dihydrosphingosine undergoes N-acylation followed by desaturation to yield a ceramide. Each one of these reactions occurs at the cytosolic surface of the endoplasmic reticulum . The ceramide is transported to the Golgi apparatus where it can be converted to sphingomyelin. Sphingomyelin synthase is responsible for the production of sphingomyelin from ceramide. Diacylglycerol

1530-434: Is reversible, and will convert excess glycine to serine. SHMT is a pyridoxal phosphate (PLP) dependent enzyme. Industrially, L -serine is produced from glycine and methanol catalyzed by hydroxymethyltransferase . Racemic serine can be prepared in the laboratory from methyl acrylate in several steps: Hydrogenation of serine gives the diol serinol : Serine is important in metabolism in that it participates in

1581-539: The actomyosin cytoskeleton which promotes contractile force generation. ROCK1 plays a role in cancer and in particular cell motility , metastasis , and angiogenesis . ROCK1 is also the name of the gene that encodes the protein ROCK1, a serine/threonine kinase. ROCK1 is activated when bound to the GTP-bound form of RhoA. The human ROCK1 gene is located on human chromosome 18 with specific location of 18q11.1. The location of

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1632-441: The biosynthesis of purines and pyrimidines . It is the precursor to several amino acids including glycine and cysteine , as well as tryptophan in bacteria. It is also the precursor to numerous other metabolites, including sphingolipids and folate , which is the principal donor of one-carbon fragments in biosynthesis. D -Serine, synthesized in neurons by serine racemase from L -serine (its enantiomer ), serves as

1683-498: The cerebrospinal fluid of probable AD patients. D-serine, which is made in the brain, has been shown to work as an antagonist/inverse co-agonist of t -NMDA receptors mitigating neuron loss in an animal model of temporal lobe epilepsy . D -Serine has been theorized as a potential treatment for sensorineural hearing disorders such as hearing loss and tinnitus . Sphingomyelin Sphingomyelin ( SPH , ˌsfɪŋɡoˈmaɪəlɪn )

1734-465: The ER and plasma membrane, with slightly higher concentrations towards the trans side. The synthesis of sphingomyelin involves the enzymatic transfer of a phosphocholine from phosphatidylcholine to a ceramide. The first committed step of sphingomyelin synthesis involves the condensation of L-serine and palmitoyl-CoA . This reaction is catalyzed by serine palmitoyltransferase . The product of this reaction

1785-458: The base pair starts at 18,529,703 and ends at 18,691,812 bp and translates into 1354 amino acids . ROCK1 has a ubiquitous tissue distribution, but subcellularly it is thought to colocalize with the centrosomes . This is consistent with its function as a key modulator of cell motility , tumor cell invasion , and actin cytoskeleton organization. In rats, ROCK1 is expressed in the lung, liver, spleen, kidney, and testis. The ROCK1 structure

1836-462: The brain, soon after the discovery of D -aspartate . Had D amino acids been discovered in humans sooner, the glycine site on the NMDA receptor might instead be named the D -serine site. Apart from central nervous system, D -serine plays a signaling role in peripheral tissues and organs such as cartilage, kidney, and corpus cavernosum. Pure D -serine is an off-white crystalline powder with

1887-422: The cell. It is a plasma membrane component and participates in many signaling pathways. The metabolism of sphingomyelin creates many products that play significant roles in the cell. Sphingomyelin consists of a phosphocholine head group, a sphingosine , and a fatty acid . It is one of the few membrane phospholipids not synthesized from glycerol. The sphingosine and fatty acid can collectively be categorized as

1938-404: The cerebrospinal fluid, particularly tumor necrosis factor alpha . This activates sphingomyelinase, an enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide; sphingomyelinase activity has been observed in conjunction with cellular apoptosis. An excess of sphingomyelin in the red blood cell membrane (as in abetalipoproteinemia ) causes excess lipid accumulation in the outer leaflet of

1989-407: The human body under normal physiological circumstances, making it a nonessential amino acid. It is encoded by the codons UCU, UCC, UCA, UCG, AGU and AGC. This compound is one of the proteinogenic amino acids . Only the L - stereoisomer appears naturally in proteins. It is not essential to the human diet, since it is synthesized in the body from other metabolites , including glycine . Serine

2040-404: The inner leaflet, further suggesting that there may be sphingomyelin present there. The function of sphingomyelin remained unclear until it was found to have a role in signal transduction . It has been discovered that sphingomyelin plays a significant role in cell signaling pathways. The synthesis of sphingomyelin at the plasma membrane by sphingomyelin synthase 2 produces diacylglycerol, which

2091-656: The kinase activation site. Experiments with Y27632 show it is a promising candidate as a therapeutic antihypertensive agent . Fasudil has been used to characterize the role of ROCK1 in vascular function in clinical studies and has been approved for use in Japan for treatment of cerebral vasospasm following subarachnoid hemorrhage . The ROCK1 signaling plays an important role in many diseases including diabetes , neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis (ALS), and pulmonary hypertension . Serine Serine (symbol Ser or S )

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2142-467: The kinase. This view of autoinhibition released by RhoA binding has been challenged by low resolution electron microscopy data showing ROCK to be a constitutive linear dimer 120 nm in length. According to this new data ROCK does not need to be activated by RhoA or phosphorylation because it is always active, and whether ROCK will phosphorylate its substrates (e.g. myosin regulatory light chain ) depends only on their subcellular localization. There

2193-414: The pathway the production of ceramide may influence either the rate and form of cell death or work to release blocks on downstream events. Sphingomyelin, as well as other sphingolipids, are associated with lipid microdomains in the plasma membrane known as lipid rafts . Lipid rafts are characterized by the lipid molecules being in the lipid ordered phase, offering more structure and rigidity compared to

2244-443: The plasticity of the tumor. By reducing the strength of cell-cell interactions and aiding the movement of tumor cells, ROCK1 may enable endothelial cells to penetrate the tumor mass more easily. ROCK1 inhibitors might be used in cancer therapy for: ROCK1 inhibition for cancer treatment has not been approved for standard therapy use. Y27632 and Fasudil are examples of ROCK1 inhibitors. Both inhibit ROCK1 by competing with ATP for

2295-586: The pleckstrin-homology domain, thus disrupting its ability to inhibit ROCK1. G-protein RhoE binds to the N-terminus of ROCK1 and inhibits its activity by preventing RhoA binding. Small G-proteins, Gem and Rad , have been shown to bind and inhibit ROCK1 function, but their mechanism of action is unclear. ROCK1 phosphorylation sites are at RXXS/T or RXS/T. More than 15 ROCK1 substrates have been identified and activation from these substrates most often leads to actin filament formation and cytoskeleton rearrangements. MYPT-1

2346-521: The pre-teen years. The brain is not affected. Most patients present with <1% normal levels of the enzyme in comparison to normal levels. A hemolytic protein, lysenin, may be a valuable probe for sphingomyelin detection in cells of Niemann-Pick A patients. As a result of the autoimmune disease multiple sclerosis (MS), the myelin sheath of neuronal cells in the brain and spinal cord is degraded, resulting in loss of signal transduction capability. MS patients exhibit upregulation of certain cytokines in

2397-652: The rest of the plasma membrane. In the rafts, the acyl chains have low chain motion but the molecules have high lateral mobility. This order is in part due to the higher transition temperature of sphingolipids as well as the interactions of these lipids with cholesterol. Cholesterol is a relatively small, nonpolar molecule that can fill the space between the sphingolipids that is a result of the large acyl chains. Lipid rafts are thought to be involved in many cell processes, such as membrane sorting and trafficking, signal transduction, and cell polarization. Excessive sphingomyelin in lipid rafts may lead to insulin resistance . Due to

2448-424: The specific types of lipids in these microdomains, lipid rafts can accumulate certain types of proteins associated with them, thereby increasing the special functions they possess. Lipid rafts have been speculated to be involved in the cascade of cell apoptosis. Sphingomyelin can accumulate in a rare hereditary disease called Niemann–Pick disease , types A and B. It is a genetically-inherited disease caused by

2499-410: Was first isolated by German chemist Johann L.W. Thudicum in the 1880s. The structure of sphingomyelin was first reported in 1927 as N-acyl-sphingosine-1-phosphorylcholine. Sphingomyelin content in mammals ranges from 2 to 15% in most tissues, with higher concentrations found in nerve tissues, red blood cells, and the ocular lenses. Sphingomyelin has significant structural and functional roles in

2550-614: Was first obtained from silk protein, a particularly rich source, in 1865 by Emil Cramer. Its name is derived from the Latin for silk, sericum . Serine's structure was established in 1902. The biosynthesis of serine starts with the oxidation of 3-phosphoglycerate (an intermediate from glycolysis ) to 3-phosphohydroxypyruvate and NADH by phosphoglycerate dehydrogenase ( EC 1.1.1.95 ). Reductive amination (transamination) of this ketone by phosphoserine transaminase ( EC 2.6.1.52 ) yields 3-phosphoserine ( O -phosphoserine) which

2601-402: Was then hypothesized that sphingomyelin hydrolysis and ceramide signaling were essential in the decision of whether a cell dies. In the early 2000s new studies emerged that defined a new role for sphingomyelin hydrolysis in apoptosis, determining not only when a cell dies but how. After more experimentation it has been shown that if sphingomyelin hydrolysis happens at a sufficiently early point in

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