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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

6347

20293

Ensembl

ENSG00000108691

ENSMUSG00000035352

UniProt

P13500

Q62401

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

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

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/ JNK–AP1 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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  32. ^ Chandrakala AN, Sukul D, Selvarajan K, Sai-Sudhakar C, Sun B, Parthasarathy S (januar 2012). "Induction of brain natriuretic peptide and monocyte chemotactic protein-1 gene expression by oxidized low-density lipoprotein: relevance to ischemic heart failure". American Journal of Physiology. Cell Physiology. 302 (1): C165-77. doi:10.1152/ajpcell.00116.2011. PMID 21900689.
  33. ^ Cuesta S, Kireev R, Forman K, García C, Escames G, Ariznavarreta C, Vara E, Tresguerres JA (decembar 2010). "Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8)". Experimental Gerontology. 45 (12): 950–6. doi:10.1016/j.exger.2010.08.016. PMID 20817086. S2CID 42491323.

Vanjski linkovi

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Dopunska literatura

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