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FLASH GENE

Symbol

CCL2

contributors: mct/ - updated : 27-01-2017

HGNC name	chemokine (C-C motif) ligand 2
HGNC id	10618

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

widely

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       moderately Digestive intestine large intestine colon   moderately   pharynx       highly Endocrine pancreas       highly Nervous spinal cord posterior horn     highly Mus musculus Adult Respiratory lung       moderately Urinary kidney       moderately Visual eye       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     moderately Connective bone     moderately

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune T cell Nervous astrocyte Mus musculus Adult

cell lineage
cell lines
fluid/secretion	blood

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

mono polymer

homomer , monomer , dimer

HOMOLOGY

interspecies

homolog to murine Ccl2 (67.37 pc)

intraspecies

homolog to SCYA7

Homologene

FAMILY	CXC subfamily of cytokines
	intercrine beta (chemokine CC) family

CATEGORY

immunity/defense , signaling cytokine , receptor membrane G

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,endoplasmic reticulum

basic FUNCTION	chemotactic factor for monocytes and basophils
	induces proliferation and interleukin-6 production in smooth muscle cells by differential activation of nuclear factor-kappa B and activator protein-1
	playing an important role in attracting monocytes to sites of inflammation, and in the recruitment and activation of monocytes during inflammation
	acting as a paracrine and autocrine factor for growth and invasion in prostate cancer
	a key molecule involved in the regulation of monocyte/macrophage immigration and activation, and therefore is involved in a broad variety of neurological and non-neurological diseases
	mediates fibroblast survival by inhibiting apoptosis through IL-6/STAT3 signaling and may contribute to the development and maintenance of lung fibrosis
	contributes to enhanced leukocyte recruitment and activation resulting in chronic damage of cardiomyocytes
	plays a critical role in the recruitment and activation of leukocytes and implicated in the regulation of osteoclast cell-cell fusion
	regulating osteoclastogenesis in an autocrine/paracrine manner under the stimulation of TNFSF11 in osteoclasts
	plays a critical role in the development of heart failure that is known to involve apoptosis
	causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing ZC3H12A
	important mediator of macrophage-related neural damage in models of two distinct inherited neuropathies
	enhances efferocytosis through RAC1 activation
	with its receptor CCR2 may contribute to neuropathic pain development
	has the typical characteristics of a neuronal mediator involved in nociceptive signal processing
	association of CCL2 with OLR1 and LPA may play a role in modulating monocyte trafficking during atherogenesis
	one of the vital chemokines that control the migration and infiltration of monocytes/macrophages
	obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis
	major role as a chemoattractant of monocytes for immunological surveillance and to site of inflammation
	mediates anti-fibrotic effects independently of CCR2 in human fibroblasts of different origins
	regulates macrophage cytotoxicity in abdominal aortic aneurysm
	CCL2/CCL3 are small chemotactic proteins that have been found in several kinds of tumor tissue samples and function as key regulators of cancer progression
	CCL2-mediated skeletal muscle macrophages recruitment plays likely a role in the etiology of Type 2 Diabetes
	RAB26, MR1, CCL2, SLC29A4, IBTK, VEGFB, and GOLGA8B may play critical roles in atherosclerotic plaque formation

CELLULAR PROCESS

cell migration & motility

PHYSIOLOGICAL PROCESS

inflammation

PATHWAY

metabolism

signaling

signal transduction

	CCL2/RAC1/PI3K pathway plays critical role in resolution of acute lung inflammation
	CCL2-CCR2 signaling may be involved in the maintenance of orofacial neuropathic pain via astroglial-neuronal interactio
	plays a key role in monocyte/macrophage recruitment and in macrophage-dependent inflammatory responses that lead to the development of atherosclerosis and insulin resistance

a component

INTERACTION

DNA

RNA

small molecule

protein	triggering JAK2 activation and tyrosine phosphorylation of CCR2-B
	binds to chemokine receptors CCR2 and CCR4
	interacting with PRKCB1 for the chemotactic response of monocytes to CCL2
	adiponectin stimulates release of CCL2, CCL3, CCL4, CCL5 in primary human monocytes, and induction in cells of overweight probands is partly impaired
	CCL2 binding to primary adult human astrocytes is CCR2-independent and is likely to be mediated via the ACKR2 decoy chemokine receptor
	PIK3CG is essential for CCL2-stimulated aortic SMC migration and amplifies cell migration induced by PDGF by an autocrine/paracrine loop involving CCL2 secretion and CCR2 activation
	CCL2/CCR2 (interaction is responsible for the infiltration of peripheral cells to the thymus in the Th1-inflammatory/infectious situations
	HDAC2 may act as a negative regulator of CCL2
	TWIST1 expression did not increase the secretion of the common proangiogenic factors VEGFA and basic fibroblast growth factor but rather induced expression of the macrophage chemoattractant CCL2
	osteoblast and osteocyte CCL2 expression is an important mediator for the anabolic effects of PTH on bone 4)
	NFKBIZ is directly recruited to the proximal promoter region of the CCL2 gene and is required for transcription-enhancing histone H3 at lysine-4 trimethylation
	OLR1 binds CCL2 and the OLR1-bound CCL2 retains its ability to recruit monocytes
	CCL2 and CCR2 have been shown to be induced and involved in various neurodegenerative disorders including Alzheimer disease, multiple sclerosis, and ischemic brain injury
	ZXDC is a regulator in the process of myeloid function and is responsible for CCL2 gene de-repression by BCL6
	OLR1 promotes migration and adhesion of bone marrow-derived mesenchymal stem cells via regulation of CCL2 expression
	NR1D1 regulates the inflammatory infiltration of macrophages through the suppression of CCL2 expression
	CCL2 modulate macrophage cytotoxicity by increasing the level of membrane bound FASLG
	FLI1 gene actively promotes transcription from the CCL2 gene promoter in a dose-dependent manner
	overexpression of TERF1 in aging endothelial cells (EC) reduced telomere-associated DNA damage foci and reduced expression levels of CCL2
	TICAM1 regulated foam cell formation via regulation of the expression levels of CCL2, F3, OLR1

cell & other

REGULATION

induced by

DLL4, inducing CCL2 expression in arteries and adipose tissues

repressed by

inhibitors selective for the subset of serine/threonine kinases, protein kinase C (PKC)

Other	upregulated by inflammatory mediators (IL-1alpha & TNF-alpha) and downregulated by hypoxia in cardiac cells
	EDN1 induces mRNA and protein secretion of CCL2 and IL6, forming an autocrine signaling pathway that stimulates collagen accumulation in the extracellular matrix
	specifically regulated during activation of skeletal repair and remodeling (

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in chronic hepatite C virus infection and in amyotrophic lateral sclerosis progressing most rapidly constitutional     --over   associated with chronic inflammation may contribute to the development of heart failure tumoral     --over   clinical association of CCL2 overexpression in human cancers with poor prognosis tumoral     --over   CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer constitutional     --over   CCL2 and CCL3 are upregulated in the injured peripheral nerve through epigenetic histone modification in infiltrating immune cells such as macrophages

Susceptibility

to severe chronic hepatite C virus infection (HCV) to pulmonary tuberculosis to idiopathic dilated cardiomyopathy (IDC)

Variant & Polymorphism other	associated with the susceptibility to RA
	2518 CCL2 G allele, may predispose HCV patients to more severe hepatic inflammation and fibrosis, and predisposing to severe pulmonary tuberculosis
	G allele at -2518 may be a novel genetic marker of susceptibility to nonfamilial IDC

Candidate gene
Marker	CCL2 and CCL3 are associated with progression of oral squamous cell carcinoma (OSCC) and may be potential biomarkers
Therapy target
	System Type Disorder Pubmed neuromuscular neuropathy   attenuation of CCL2 upregulation by inhibition of ERK phosphorylation appears to be a most promising approach to treat a broader spectrum of inherited peripheral neuropathies diabete     use of therapeutic strategies aimed at antagonizing CCL2 or IL6 signaling in diabetic kidney injury miscelleaneous pain   antagonists of CCL2/CCR2 are promising agents from treating neuropathic pain. miscelleaneous pain   targeting CCL2-CCR2 signaling may be a potentially important new treatment strategy for trigeminal neuralgia

ANIMAL & CELL MODELS

	Mcp1 -/- mice synthesized extremely low levels of interleukin-4, interleukin-5, and interleukin-10
	in Gjb1-deficient mice (Cx32def), Ccl2 is upregulated in a MEK–ERK-dependent manner (CCL2 reduction is a promising strategy to treat CMT1 neuropathies, particularly in disease forms where axon damage is predominant as in Cx32def mice and the corresponding human disorder, CMT1X)
	macrophages from Ccr2-null mice were not capable of promoting trans-endothelial migration of tumour cells