Selectin

The selectins (cluster of differentiation 62 or CD62) are a family of

cell adhesion molecules (or CAMs). All selectins are single-chain
Selectin
transmembrane glycoproteins that share similar properties to C-type
lectins due to a related amino terminus and calcium-dependent
binding.[2] Selectins bind to sugar moieties and so are considered to
be a type of lectin, cell adhesion proteins that bind sugar polymers.[3]

Contents
Structure
Types
Etymology
Function
Bonding mechanisms
Role in cancer
Organ selectivity
Crystallographic structure of P-
Research selectin lectin bound to sugar,
See also shown in sticks.[1]
References Identifiers
External links Symbol Selectin
InterPro IPR002396 (https://
www.ebi.ac.uk/inter
Structure pro/entry/IPR00239
6)
All three known members of the selectin family (L-, E-, and P-
selectin) share a similar cassette structure: an N-terminal, calcium- Membranome 12 (http://membran
dependent lectin domain, an epidermal growth factor (EGF)-like ome.org/protein_su
domain, a variable number of consensus repeat units (2, 6, and 9 for perfamilies/12)
L-, E-, and P-selectin, respectively), a transmembrane domain (TM)
and an intracellular cytoplasmic tail (cyto). The transmembrane and cytoplasmic parts are not conserved across
the selectins being responsible for their targeting to different compartments.[4] Though they share common
elements, their tissue distribution and binding kinetics are quite different, reflecting their divergent roles in
various pathophysiological processes.[5]

Types
There are three subsets of selectins:

E-selectin (in endothelial cells)

L-selectin (in leukocytes)
P-selectin (in platelets and endothelial cells)
L-selectin is the smallest of the vascular selectins, expressed on all granulocytes and monocytes and on most
lymphocytes, can be found in most leukocytes. P-selectin, the largest selectin, is stored in α-granules of
platelets and in Weibel–Palade bodies of endothelial cells, and is translocated to the cell surface of activated
endothelial cells and platelets. E-selectin is not expressed under baseline conditions, except in skin
microvessels, but is rapidly induced by inflammatory cytokines.

These three types share a significant degree of sequence homology among themselves (except in the
transmembrane and cytoplasmic domains) and between species. Analysis of this homology has revealed that
the lectin domain, which binds sugars, is most conserved, suggesting that the three selectins bind similar sugar
structures. The cytoplasmic and transmembrane domains are highly conserved between species, but not
conserved across the selectins. These parts of the selectin molecules are responsible for their targeting to
different compartments: P-selectin to secretory granules, E-selectin to the plasma membrane, and L-selectin to
the tips of microfolds on leukocytes.[4]

Etymology
The name selectin comes from the words "selected" and "lectins," which are a type of carbohydrate-
recognizing protein.[6]

Function
Selectins are involved in constitutive lymphocyte homing, and in chronic and acute inflammation processes,
including post-ischemic inflammation in muscle, kidney and heart, skin inflammation, atherosclerosis,
glomerulonephritis and lupus erythematosus[4] and cancer metastasis.

During an inflammatory response, P-selectin is expressed on endothelial cells first, followed by E-selectin later.
Stimuli such as histamine and thrombin cause endothelial cells to mobilize immediate release of preformed P-
selectin from Weible-Palade bodies inside the cell. Cytokines such as TNF-alpha stimulate transcription and
translation of E-selectin and additional P-selection, which account for the delay of several hours.[7]

As the leukocyte rolls along the blood vessel wall, the distal lectin-like domain of the selectin binds to certain
carbohydrate groups presented on proteins (such as PSGL-1) on the leukocyte, which slows the cell and
allows it to leave the blood vessel and enter the site of infection. The low-affinity nature of selectins is what
allows the characteristic "rolling" action attributed to leukocytes during the leukocyte adhesion cascade.[2]

Each selectin has a carbohydrate recognition domain that mediates binding to specific glycans on apposing
cells. They have remarkably similar protein folds and carbohydrate binding residues,[1] leading to overlap in
the glycans to which they bind.

Selectins bind to the sialyl Lewis X (SLex ) determinant “NeuAcα2-3Galβ1-4(Fucα1-3)GlcNAc.” However,

SLex , per se, does not constitute an effective selectin receptor. Instead, SLex and related sialylated, fucosylated
glycans are components of more extensive binding determinants.[8]

The best-characterized ligand for the three selectins is P-selectin glycoprotein ligand-1 (PSGL-1), which is a
mucin-type glycoprotein expressed on all white blood cells.

Neutrophils and eosinophils bind to E-selectin. One of the reported ligands for E-selectin is the sialylated
Lewis X antigen (SLex ). Eosinophils, like neutrophils, use sialylated, protease-resistant structures to bind to E-
selectin, although the eosinophil expresses much lower levels of these structures on its surface.[9]
Ligands for P-selectin on eosinophils and neutrophils are similar sialylated, protease-sensitive, endo-beta-
galactosidase-resistant structures, clearly different than those reported for E-selectin, and suggest disparate
roles for P-selectin and E-selectin during recruitment during inflammatory responses.[10]

Bonding mechanisms
Selectins have hinge domains, allowing them to undergo rapid conformational changes in the nanosecond
range between ‘open’ and ‘closed’ conformations. Shear stress on the selectin molecule causes it to favor the
‘open’ conformation.[11]

In leukocyte rolling, the ‘open’ conformation of the selectin allows it to bind to inward sialyl Lewis molecules
farther up along the PSGL-1 chain, increasing overall binding affinity—if the selectin-sialyl Lewis bond
breaks, it can slide and form new bonds with the other sialyl Lewis molecules down the chain. In the ‘closed’
conformation, however, the selectin is only able to bind to one sialyl Lewis molecule, and thus has greatly
reduced binding affinity.

The result of such is that selectins exhibit catch and slip bond behavior—under low shear stresses, their
bonding affinities are actually increased by an increase in tensile force applied to the bond because of more
selectins preferring the ‘open’ conformation. At high stresses, the binding affinities are still reduced because
the selectin-ligand bond is still a normal slip bond. It is thought that this shear stress threshold helps select for
the right diameter of blood vessels to initiate leukocyte extravasation, and may also help prevent inappropriate
leukocyte aggregation during vascular stasis.[12]

Role in cancer
It is becoming evident that selectin may play a role in inflammation and progression of cancer.[4] Tumor cells
exploit the selectin-dependent mechanisms mediating cell tethering and rolling interactions through recognition
of carbohydrate ligands on tumor cell to enhance distant organ metastasis,[13][14] showing ‘leukocyte
mimicry’.[15]

A number of studies have shown increased expression of carbohydrate ligands on metastatic tumor,[16]
enhanced E-selectin expression on the surface of endothelial vessels at the site at tumor metastasis,[17] and the
capacity of metastatic tumor cells to roll and adhere to endothelial cells, indicating the role of selectins in
metastasis.[18] In addition to E-selectin, the role of P-selectin (expressed on platelets) and L-selectin (on
leukocytes) in cancer dissemination has been suggested in the way that they interact with circulating cancer
cells at an early stage of metastasis.[19][20]

Organ selectivity

The selectins and selectin ligands determine the organ selectivity of metastasis. Several factors may explain the
seed and soil theory or homing of metastasis. In particular, genetic regulation and activation of specific
chemokines, cytokines and proteases may direct metastasis to a preferred organ. In fact, the extravasation of
circulating tumor cells in the host organ requires successive adhesive interactions between endothelial cells and
their ligands or counter-receptors present on the cancer cells. Metastatic cells that show a high propensity to
metastasize to certain organs adhere at higher rates to venular endothelial cells isolated from these target sites.
Moreover, they invade the target tissue at higher rates and respond better to paracrine growth factors released
from the target site.
Typically, the cancer cell/endothelial cell interactions imply first a selectin-mediated initial attachment and
rolling of the circulating cancer cells on the endothelium. The rolling cancer cells then become activated by
locally released chemokines present at the surface of endothelial cells. This triggers the activation of integrins
from the cancer cells allowing their firmer adhesion to members of the Ig-CAM family such as ICAM,
initiating the transendothelial migration and extravasation processes.[72]

The appropriate set of endothelial receptors is sometimes not expressed constitutively and the cancer cells have
to trigger their expression. In this context, the culture supernatants of cancer cells can trigger the expression of
E- selectin by endothelial cells suggesting that cancer cells may release by themselves cytokines such as TNF-
α, IL-1β or INF-γ that will directly activate endothelial cells to express E-selectin, P-selectin, ICAM-2 or
VCAM. On the other hand, several studies further show that cancer cells may initiate the expression of
endothelial adhesion molecules in a more indirect ways.

Since the adhesion of several cancer cells to endothelium requires the presence of endothelial selectins as well
as sialyl Lewis carbohydrates on cancer cells, the degree of expression of selectins on the vascular wall and the
presence of the appropriate ligand on cancer cells are determinant for their adhesion and extravasation into a
specific organ. The differential selectin expression profile on endothelium and the specific interactions of
selectins expressed by endothelial cells of potential target organs and their ligands expressed on cancer cells
are major determinants that underlie the organ-specific distribution of metastases.

Research
Selectins are involved in projects to treat osteoporosis, a disease that occurs when bone-creating cells called
osteoblasts become too scarce. Osteoblasts develop from stem cells, and scientists hope to eventually be able to
treat osteoporosis by adding stem cells to a patient’s bone marrow. Researchers have developed a way to use
selectins to direct stem cells introduced into the vascular system to the bone marrow.[21] E-selectins are
constitutively expressed in the bone marrow, and researchers have shown that tagging stem cells with a certain
glycoprotein causes these cells to migrate to the bone marrow. Thus, selectins may someday be essential to a
regenerative therapy for osteoporosis.[22]

See also
Sushi domain

References
1. PDB: 1G1R (https://www.rcsb.org/structure/1G1R); Somers WS, Tang J, Shaw GD,
Camphausen RT (October 2000). "Insights into the molecular basis of leukocyte tethering and
rolling revealed by structures of P- and E-selectin bound to SLe(X) and PSGL-1". Cell. 103 (3):
467–79. doi:10.1016/S0092-8674(00)00138-0 (https://doi.org/10.1016%2FS0092-8674%280
0%2900138-0). PMID 11081633 (https://pubmed.ncbi.nlm.nih.gov/11081633).
2. Cotran; Kumar, Collins (1998). Robbins Pathologic Basis of Disease. Philadelphia: W.B
Saunders Company. ISBN 978-0-7216-7335-6.
3. Parham, Peter (2005). The immune system (https://archive.org/details/immunesystem00parh/pa
ge/244) (2nd ed.). New York: Garland Science. pp. 244–245 (https://archive.org/details/immune
system00parh/page/244). ISBN 978-0-8153-4093-5.
4. Ley K (June 2003). "The role of selectins in inflammation and disease". Trends in Molecular
Medicine. 9 (6): 263–8. CiteSeerX 10.1.1.407.6232 (https://citeseerx.ist.psu.edu/viewdoc/summ
ary?doi=10.1.1.407.6232). doi:10.1016/S1471-4914(03)00071-6 (https://doi.org/10.1016%2FS
1471-4914%2803%2900071-6). PMID 12829015 (https://pubmed.ncbi.nlm.nih.gov/12829015).
 5. Cheung LS, Raman PS, Balzer EM, Wirtz D, Konstantopoulos K (February 2011). "Biophysics
of selectin-ligand interactions in inflammation and cancer". Physical Biology. 8 (1): 015013.
Bibcode:2011PhBio...8a5013S (https://ui.adsabs.harvard.edu/abs/2011PhBio...8a5013S).
doi:10.1088/1478-3975/8/1/015013 (https://doi.org/10.1088%2F1478-3975%2F8%2F1%2F015
013). PMID 21301059 (https://pubmed.ncbi.nlm.nih.gov/21301059).
6. Kappelmayer J, Nagy B (2017). "The Interaction of Selectins and PSGL-1 as a Key Component
in Thrombus Formation and Cancer Progression" (https://www.ncbi.nlm.nih.gov/pmc/articles/P
MC5478826). BioMed Research International. 2017: 6138145. doi:10.1155/2017/6138145 (http
s://doi.org/10.1155%2F2017%2F6138145). PMC 5478826 (https://www.ncbi.nlm.nih.gov/pmc/a
rticles/PMC5478826). PMID 28680883 (https://pubmed.ncbi.nlm.nih.gov/28680883).
7. Jennette, J. Charles; Falk, Ronald J. (2008). "Immunologic Mechanisms of Vasculitis". Seldin
and Giebisch's the Kidney. pp. 2315–2338. doi:10.1016/B978-012088488-9.50085-1 (https://do
i.org/10.1016%2FB978-012088488-9.50085-1). ISBN 9780120884889.
8. Nimrichter L, Burdick MM, Aoki K, Laroy W, Fierro MA, Hudson SA, Von Seggern CE, Cotter
RJ, Bochner BS, Tiemeyer M, Konstantopoulos K, Schnaar RL (November 2008). "E-selectin
receptors on human leukocytes" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572800).
Blood. 112 (9): 3744–52. doi:10.1182/blood-2008-04-149641 (https://doi.org/10.1182%2Fblood
-2008-04-149641). PMC 2572800 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572800).
PMID 18579791 (https://pubmed.ncbi.nlm.nih.gov/18579791).
9. Bochner BS, Sterbinsky SA, Bickel CA, Werfel S, Wein M, Newman W (January 1994).
"Differences between human eosinophils and neutrophils in the function and expression of
sialic acid-containing counterligands for E-selectin". Journal of Immunology. 152 (2): 774–82.
PMID 7506734 (https://pubmed.ncbi.nlm.nih.gov/7506734).
10. Wein M, Sterbinsky SA, Bickel CA, Schleimer RP, Bochner BS (March 1995). "Comparison of
human eosinophil and neutrophil ligands for P-selectin: ligands for P-selectin differ from those
for E-selectin". American Journal of Respiratory Cell and Molecular Biology. 12 (3): 315–9.
doi:10.1165/ajrcmb.12.3.7532979 (https://doi.org/10.1165%2Fajrcmb.12.3.7532979).
PMID 7532979 (https://pubmed.ncbi.nlm.nih.gov/7532979).
11. Thomas W (September 2006). "For catch bonds, it all hinges on the interdomain region" (http
s://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064382). The Journal of Cell Biology. 174 (7):
911–3. doi:10.1083/jcb.200609029 (https://doi.org/10.1083%2Fjcb.200609029). PMC 2064382
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064382). PMID 17000873 (https://pubmed.ncb
i.nlm.nih.gov/17000873).
12. Yago T, Wu J, Wey CD, Klopocki AG, Zhu C, McEver RP (September 2004). "Catch bonds
govern adhesion through L-selectin at threshold shear" (https://www.ncbi.nlm.nih.gov/pmc/articl
es/PMC2172126). The Journal of Cell Biology. 166 (6): 913–23. doi:10.1083/jcb.200403144 (ht
tps://doi.org/10.1083%2Fjcb.200403144). PMC 2172126 (https://www.ncbi.nlm.nih.gov/pmc/arti
cles/PMC2172126). PMID 15364963 (https://pubmed.ncbi.nlm.nih.gov/15364963).
13. Barthel SR, Gavino JD, Descheny L, Dimitroff CJ (November 2007). "Targeting selectins and
selectin ligands in inflammation and cancer" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC25
59865). Expert Opinion on Therapeutic Targets. 11 (11): 1473–91.
doi:10.1517/14728222.11.11.1473 (https://doi.org/10.1517%2F14728222.11.11.1473).
PMC 2559865 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2559865). PMID 18028011 (http
s://pubmed.ncbi.nlm.nih.gov/18028011).
14. St Hill CA (June 2011). "Interactions between endothelial selectins and cancer cells regulate
metastasis". Frontiers in Bioscience. 16: 3233–51. doi:10.2741/3909 (https://doi.org/10.2741%2
F3909). PMID 21622232 (https://pubmed.ncbi.nlm.nih.gov/21622232).
15. Witz IP (2006). "Tumor-Microenvironment Interactions". Tumor-microenvironment interactions:
the selectin-selectin ligand axis in tumor-endothelium cross talk. Cancer Treatment and
Research. 130. pp. 125–40. doi:10.1007/0-387-26283-0_6 (https://doi.org/10.1007%2F0-387-2
6283-0_6). ISBN 978-0-387-26282-6. PMID 16610706 (https://pubmed.ncbi.nlm.nih.gov/16610
706).
16. Nakamori S, Kameyama M, Imaoka S, Furukawa H, Ishikawa O, Sasaki Y, Izumi Y, Irimura T
(April 1997). "Involvement of carbohydrate antigen sialyl Lewis(x) in colorectal cancer
metastasis". Diseases of the Colon and Rectum. 40 (4): 420–31. doi:10.1007/BF02258386 (htt
ps://doi.org/10.1007%2FBF02258386). PMID 9106690 (https://pubmed.ncbi.nlm.nih.gov/91066
90).
17. Matsuura N, Narita T, Mitsuoka C, Kimura N, Kannagi R, Imai T, Funahashi H, Takagi H (1997).
"Increased concentration of soluble E-selectin in the sera of breast cancer patients". Anticancer
Research. 17 (2B): 1367–72. PMID 9137500 (https://pubmed.ncbi.nlm.nih.gov/9137500).
18. Gout S, Morin C, Houle F, Huot J (September 2006). "Death receptor-3, a new E-Selectin
counter-receptor that confers migration and survival advantages to colon carcinoma cells by
triggering p38 and ERK MAPK activation" (https://doi.org/10.1158/0008-5472.CAN-05-4605).
Cancer Research. 66 (18): 9117–24. doi:10.1158/0008-5472.CAN-05-4605 (https://doi.org/10.1
158%2F0008-5472.CAN-05-4605). PMID 16982754 (https://pubmed.ncbi.nlm.nih.gov/1698275
4).
19. Borsig L, Wong R, Hynes RO, Varki NM, Varki A (February 2002). "Synergistic effects of L- and
P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate
leukocytes as enhancers of metastasis" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234
1). Proceedings of the National Academy of Sciences of the United States of America. 99 (4):
2193–8. Bibcode:2002PNAS...99.2193B (https://ui.adsabs.harvard.edu/abs/2002PNAS...99.21
93B). doi:10.1073/pnas.261704098 (https://doi.org/10.1073%2Fpnas.261704098).
PMC 122341 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC122341). PMID 11854515 (https://
pubmed.ncbi.nlm.nih.gov/11854515).
20. Peeters CF, Ruers TJ, Westphal JR, de Waal RM (February 2005). "Progressive loss of
endothelial P-selectin expression with increasing malignancy in colorectal cancer" (https://doi.o
rg/10.1038/labinvest.3700217). Laboratory Investigation; A Journal of Technical Methods and
Pathology. 85 (2): 248–56. doi:10.1038/labinvest.3700217 (https://doi.org/10.1038%2Flabinves
t.3700217). PMID 15640834 (https://pubmed.ncbi.nlm.nih.gov/15640834).
21. In the lab of Robert Sackstein Harvard University
22. Sackstein Lab (http://sacksteinlab.bwh.harvard.edu/)

External links
Sackstein Lab of Research (http://sacksteinlab.bwh.harvard.edu/)
Computer-generated movie of the mobilization of P-selectin inside a leukocyte at
mcb.harvard.edu (http://multimedia.mcb.harvard.edu)

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