E-selectin
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Location (UCSC) | Chr 1: 169.72 – 169.76 Mb | Chr 1: 163.88 – 163.89 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a
Structure
E selectin has a cassette structure: an
Gene and regulation
In humans, E-selectin is encoded by the SELE gene. Its C-type lectin domain, EGF-like, SCR repeats, and transmembrane domains are each encoded by separate exons, whereas the E-selectin cytosolic domain derives from two exons. The E-selectin locus flanks the L-selectin locus on chromosome 1.[8]
Different from
Shear forces are also found to affect E-selectin expression. A high laminar shear enhances acute endothelial cell response to interleukin-1β in naïve or shear-conditioned endothelial cells as may be found in the pathological setting of ischemia/reperfusion injury while conferring rapid E-selectin down regulation to protect against chronic inflammation.[11]
Phytoestrogens, plant compounds with estrogen-like biological activity, such as genistein, formononetin, biochanin A and daidzein, as well as a mixture of these phytoestrogens were found able to reduce E-selectin as well as VCAM-1 and ICAM-1 on cell surface and in culture supernatant.[12]
Ligands
E-selectin recognizes and binds to sialylated carbohydrates present on the surface proteins of certain
These carbohydrates include members of the
The glycoprotein ESL-1, present on neutrophils and myeloid cells, was the first counter-receptor for E-selectin to be described. It is a variant of the tyrosine kinase FGF glycoreceptor, raising the possibility that its binding to E-selectin is involved in initiating signaling in the bound cells.
Both ESL-1 and PSGL-1 should bear sialyl Lewis a/x in order to bind E/P-selectins.[15]
E-selectin is found to mediate the adhesion of tumor cells to endothelial cells, by binding to E-selectin ligands on the tumor cells. E-selectin ligands also play a role in cancer metastasis. The role of these two E-selectin ligands in metastasis in vivo is poorly defined and remains to be firmly demonstrated. PSGL-1 was detected on the surfaces of bone-metastatic prostate tumor cells, suggesting that it may have a functional role in the bone tropism of prostate tumor cells.[16]
In cancer cells,
On human neutrophils the glycosphingolipid NeuAcα2-3Galβ1-4GlcNAcβ1-3[Galβ1-4(Fucα1-3)GlcNAcβ1-3]2[Galβ1-4GlcNAcβ1-3]2Galβ1-4GlcβCer (and closely related structures) are functional E-selectin receptors.[21]
Function
Role in inflammation
During
As the inflammatory response progresses, chemokines released by injured tissue enter the blood vessels and activate the rolling leukocytes, which are now able to tightly bind to the endothelial surface and begin making their way into the tissue.[13]
P-selectin has a similar function, but is expressed on the endothelial cell surface within minutes as it is stored within the cell rather than produced on demand.[13]
Role in cancer
E-selectin was first discovered as an transmembrane receptor induced in endothelial cells upon inflammatory stimulation which mediated adhesion of monocytic or HL60 leukemic cells.
While numerous pieces of in vitro and clinical evidence continue to support this hypothesis of E-selectin-mediated cancer metastasis, in vivo studies of cancer metastasis have shown that E-selectin knockout only minimally affects leukemic cell adhesion to bone immediately following injection.[31] while experimental lung metastasis is not affected by the genetic deletion of E-selectin.[32][33] Furthermore, studies have also shown that primary tumor growth is increased in E-selectin knockout mice.[34][35] This paradox was more recently solved by a trio of studies showing that E-selectin is only constitutively expressed in the bone marrow endothelium[36] where it is thought to perform functions vital to hematopoiesis.[37] that are hijacked specifically by cells metastasizing to bone and not other sites.[38] This data supports ongoing clinical efforts to inhibit breast cancer bone metastasis with E-selectin-blocking agents.[39] The complexity of E-selectin ligand biology may also play a role in these discrepant in vitro and in vivo results. At least 15 different glycoprotein and glycolipid substrates for E-selectin have been described on various cancer cells, while only n-glycan Glg1 (Esl1) was shown to mediate bone metastasis.[40] Other ligands or combinations thereof may result in distinct mechanisms during cancer metastasis.
Beyond a direct interaction with tumor cells, E-selectin induction in response to cytokines locally secreted by cancer cells enables specific tumor targeting of sLeX-conjugated nanoparticles or thioaptamers containing anti-tumor payloads.
Pathological relevance
Critical illness polyneuromyopathy
In cases of elevated blood glucose levels, such as in sepsis, E-selectin expression is higher than normal, resulting in greater microvascular permeability. The greater permeability leads to edema (swelling) of the skeletal endothelium (blood vessel linings), resulting in skeletal muscle ischemia (restricted blood supply) and eventually necrosis (cell death). This underlying pathology is the cause of the symptomatic disease critical illness polyneuromyopathy (CIPNM).[43] Traditional Chinese herbal medicines, like berberine downregulate E-selectin.[44]
Pathogen attachment
Study shows the adherence of
Acute coronary syndrome
The immunohistochemical expressions of E-selectin and
Nicotine-mediated induction
Smoking is highly correlated with enhanced likelihood of atherosclerosis by inducing endothelial dysfunction. In endothelial cells, various cell-adhesion molecules including E-selectin, are shown to be upregulated upon exposure to nicotine, the addictive component of tobacco smoke. Nicotine-stimulated adhesion of monocytes to endothelial cells is dependent on the activation of α7-nAChRs, β-Arr1 and cSrc regulated increase in E2F1-mediated transcription of E-selectin gene. Therefore, agents such as RRD-251 that can target activity of E2F1 may have potential therapeutic benefit against cigarette smoke induced atherosclerosis.[47]
Cerebral aneurysm
It's also found that E-selectin expression increased in human ruptured
As a biomarker
E-selectin is also an emerging biomarker for the metastatic potential of some cancers including colorectal cancer and recurrences.[49]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000007908 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026582 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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External links
- E-Selectin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)