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CCL2

S Wikipedije, slobodne enciklopedije
CCL2
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1DOK, 1DOL, 1DOM, 1DON, 1ML0, 2BDN, 2NZ1, 4DN4, 3IFD, 4R8I, 4ZK9

Identifikatori
AliasiCCL2
Vanjski ID-jeviOMIM: 158105 MGI: 108224 HomoloGene: 2245 GeneCards: CCL2
Lokacija gena (čovjek)
Hromosom 17 (čovjek)
Hrom.Hromosom 17 (čovjek)[1]
Hromosom 17 (čovjek)
Genomska lokacija za CCL2
Genomska lokacija za CCL2
Bend17q12Početak34,255,274 bp[1]
Kraj34,257,208 bp[1]
Lokacija gena (miš)
Hromosom 11 (miš)
Hrom.Hromosom 11 (miš)[2]
Hromosom 11 (miš)
Genomska lokacija za CCL2
Genomska lokacija za CCL2
Bend11 C|11 49.9 cMPočetak81,992,671 bp[2]
Kraj81,994,226 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija signaling receptor binding
protein kinase activity
cytokine activity
GO:0001948, GO:0016582 vezivanje za proteine
chemokine activity
CCR2 chemokine receptor binding
CCR chemokine receptor binding
Ćelijska komponenta extracellular region
Vanćelijsko
intracellular anatomical structure
Biološki proces GO:1904089 negative regulation of neuron apoptotic process
viral genome replication
negative regulation of natural killer cell chemotaxis
protein phosphorylation
cell surface receptor signaling pathway
humoral immune response
Angiogeneza
positive regulation of ERK1 and ERK2 cascade
animal organ morphogenesis
cellular homeostasis
cellular response to fibroblast growth factor stimulus
GO:0032320, GO:0032321, GO:0032855, GO:0043089, GO:0032854 positive regulation of GTPase activity
inflammatory response
G protein-coupled receptor signaling pathway
monocyte chemotaxis
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
GO:1904579 cellular response to organic cyclic compound
Hemotaksija
Ćelijska adhezija
GO:0046730, GO:0046737, GO:0046738, GO:0046736 Imuni odgovor
regulation of cell shape
lipopolysaccharide-mediated signaling pathway
receptor signaling pathway via JAK-STAT
response to bacterium
protein kinase B signaling
astrocyte cell migration
negative regulation of glial cell apoptotic process
PERK-mediated unfolded protein response
MAPK cascade
positive regulation of calcium ion import
cytoskeleton organization
GO:0072468 Transdukcija signala
regulation of signaling receptor activity
neutrophil chemotaxis
helper T cell extravasation
macrophage chemotaxis
positive regulation of T cell activation
positive regulation of nitric-oxide synthase biosynthetic process
chemokine-mediated signaling pathway
cellular response to lipopolysaccharide
cellular response to interferon-gamma
cellular response to interleukin-1
cellular response to tumor necrosis factor
positive regulation of apoptotic cell clearance
cytokine-mediated signaling pathway
negative regulation of vascular endothelial cell proliferation
GO:1990376 negative regulation of G1/S transition of mitotic cell cycle
positive regulation of endothelial cell apoptotic process
eosinophil chemotaxis
lymphocyte chemotaxis
Nocicepcija
positive regulation of synaptic transmission, glutamatergic
positive regulation of NMDA glutamate receptor activity
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_002982

NM_011331

RefSeq (bjelančevina)

NP_002973

NP_035461

Lokacija (UCSC)Chr 17: 34.26 – 34.26 MbChr 11: 81.99 – 81.99 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Hemokinski (C-C motivni) ligand 2 (CCL2) , znan i kao monocitni hemoatraktantni protein 1 (MCP1) i mali inducibilni citokin A2. CCL2 je mali citokin koji pripada porodici CC hemokina. CCL2 regrutuje monocite, memorijske T-ćelije i dendritske ćelije na mjesta upala nastalih ozljedom tkiva ili infekcijom.[5][6]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 99 aminokiselina, a molekulska težina

11.025 Da.[7].

Simboli
1020304050
MKVSAALLCLLLIAATFIPQGLAQPDAINAPVTCCYNFTNRKISVQRLAS
YRRITSSKCPKEAVIFKTIVAKEICADPKQKWVQDSMDHLDKQTQTPKT

Molekulska biologija

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CCL2 je monomerni polipeptid, sa molekulskom težinom od približno 13-15 kDa, ovisno o nivoima glikozilacije.[8] CCL2 je usidren u plazemamembranu endotelnih ćelija, pomoću bočnih lanaca glikozaminoglikanskih proteoglikana. CCL2 se primarno izlučuje iz monocita, makrofaga i dendritskih ćelija. Glavni je induktor gena CCL2 je faktor rasta izveden iz trombocita.

Na površini ćelije, CCR2 i CCR4 su dva receptora koji vežu CCL2.[9]

CCL2 ima hemotaksijsku aktivnost za monocite i bazofile. Međutim, ne privlači neutrofile ili eozinofili. Nakon delecije N-terminalnog ostatka, CCL2 gubi atraktivnost za bazofile i postaje hemoatraktant eozinofila. Bazofili i mastociti koji se liječe CCL2-om, oslobađaju svoje granule u međućelijski prostor. Ovaj se efekt može pojačati i prethodnim tretmanom IL-3 ili čak drugim citokinima.[10][11] CCL2 pojačava antitumorsku aktivnost monocita i neophodan je za stvaranje granuloma 12. CCL2 protein postaje CCR2 antagonist kada se cijepi pomoću metaloproteinaza MMP-12.[12]

CCL2 može se naći na mjestima nicanja zuba i propadanja kostiju. U kosti se CCL2 eksprimira sa zrelim osteoklastom i osteoblastom i pod nadzorom je nuklearnog faktora κB (NFκB). U ljudskim osteoklastima, CCL2 i RANTES (regulirani na aktivaciju normalnih eksprimiranih i izlučenih T-ćelija). I MCP-1 i RANTES indukuju stvaranje TRAP-pozitivnih, multijedarnih ćelija iz monocita tretiranih M-CSF u odsustvu RANKL-a, ali su stvorili osteoklaste kojima nedostaje ekspresija katepsina K i resorptivna sposobnost. Predlaže se da CCL2 i RANTES djeluju kao autokrina petlja u diferencijaciji ljudskih osteoklasta.[13]

Hemokin CCL2 također eksprimiraju neuroni, astrociti i mikroglija. Ekspresija CCL2 u neuronima uglavnom je u moždanom korteksu, globus pallidus, hipokampusu, parakomorskim i supraoptičnim hipotalamusnim jezgrima, bočnim dijelovima hipotalamusa, substantia nigra, jezgrima lica, motornim i kičmenim trigeminusnim jezgrima, gigantoćelijskom mrežastom jezgru i u Purkinjeovim ćelijama u malom mozgu.[14]

Genomika

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U ljudskom genomu, CCL2 i geni mnogih drugih CC hemokina nalaze se na hromosomu 17 (17q11.2-q21.1).[15] Raspon gena je 1.927 baza, a CCL2 gen nalazi se na lancu Watson (plus). Gen CCL2 ima tri egzona i dva introna. Proteinski prekursor CCL2 sadrži signalni peptid od 23 aminokiseline. Zreli CCL2 dug je 76 aminokiselina.[16][17] Predviđena težina CCL2 je 11,025 kiloDaltona (kDa).

Populacijska genetika

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U ljudi, nivo CCL2 može znatno varirati. Kod kavkazoida evropskog porijekla multivarijabilno prilagođena nasljednost koncentracija CCL2 iznosi čak 0,37 u krvnoj plazmi i 0,44 – u serumu.[18][19]

Klinički značaj

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CCL2 je uključen u patogeneze nekoliko bolesti koje karakterišu monocitni infiltrati, kao što su psorijaza, reumatoidni artritis i ateroskleroza.[20]

Primjena antitijela na CCL2 u modelu glomerulonefritis smanjuje infiltraciju makrofaga i T-ćelija, smanjuje stvaranje polumjesečastih struktura, kao i ožiljke i oštećenje bubrega.[21]

CCL2 je uključen u neuroupalne procese koji se odvijaju kod različitih bolesti centralnog nervnog sistema (CNS), koje karakterizira degeneracija neurona.[22] Ekspresija CCL2 u ćelijama glije povećana je kod epilepsije,[23][24] ishemije mozga[25] Alzhrimerove bolesti[26] eksperimentalnog autoimunskog encefalomijelitisa (EAE)[27] i taumatske povrede mozga.[28]

Na hipometilaciju CpG mjesta unutar promotorske regije CCL2 utiču visoki nivoi glukoze u krvi i TG, koji povećavaju nivo CCL2 u krvnom serumu. Kasnije ima važnu ulogu u vaskularnim komplikacijama dijabetesa tipa 2.[29]

CCL2 indukcira ekspresiju amilina, oputem MAPK3 ERK1/ERK2/ JNKAP1 i NF-κB povezanih signalnih puteva neovisnih o CCR2. Povećanje regulacije amilina pomoću CCL2 doprinosi povišenju rezistencije aminina u plazmi i rezistencije na insulin kod gojaznosti.[30]

Adipociti luče različite adipokine, koji mogu biti uključeni u negativni unakrsni odgovor između masnog tkiva i skeletnih mišića. CCL2 umanjuje signal inzulina u ćelijama skeletnih mišića aktiviranjem ERK1/2 u dozama sličnim njegovim fiziološkim koncentracijama u plazmi (200 pg/ml), ali ne uključuje aktivaciju NF-κB puta. CCL2 je značajno smanjio unos glukoze stimuliran insulinom u miocitima. CCL2 može predstavljati molekulsku vezu u negativnom unakrsnom odgovoru između masnog tkiva i koštanog mišića, dodijelivši CCL2 potpuno novu važnu ulogu osim upala.[31]

Inkubacija HL-1 kardiomiocita i ljudskih miocita sa oksidovanim LDL inducirala je ekspresiju moždani natriuretski peptid (BNP) i gena CCL2, dok nativni LDL (N-LDL) nije imao efekta.[32]

Tretman melatoninom kod starih miševa sa starosnom upalom jetre smanjio je ekspresiju iRNK TNF-α, IL-1β, HO (HO-1 i HO-2), iNOS, CCL2, NF-κB1, NF-κB2 i NKAP kod starih muških miševa . Ekspresija proteina TNF-α, IL-1β također je smanjena i povećana IL-10 liječenjem melatoninom. Egzogena primjena melatonina uspjela je smanjiti upalu.[33]

Reference

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Vanjski linkovi

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Dopunska literatura

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