29.5:
Selectins
Selectins are cell surface glycoproteins that bind carbohydrate ligands and participate in transient cell-cell adhesion.
All selectins comprise an N-terminal lectin domain and an epidermal growth factor or EGF domain that regulate binding specificity and strength.
However, the number of sequence-conserved-repeats or SCR domains can vary from two to nine repeats depending on the type of selectin.
The short L-selectins expressed on immune cells like lymphocytes help them migrate into lymph nodes by binding ligands on the endothelial cells.
The larger P-selectins are primarily expressed on platelets. They aid in aggregating platelets and immune cells at the site of injury.
A third type, called E-selectins, is temporally expressed along with P-selectins on endothelial cells during an immune response.
These selectins form weak, transient interactions with free-flowing leukocytes and slow them down.
The leukocytes then roll along the endothelial surface, where other cell adhesion molecules help recruit them to the appropriate tissue microenvironments — a process called leukocyte homing.
29.5:
Selectins
Cell adhesion is an essential aspect of multicellularity. While stable cell interactions usually occur between cells of the same type, transient cell interactions occur between cells of different tissue types, such as between neutrophils and endothelial cells. Selectins are one class of cell adhesion molecules (CAMs) that bind carbohydrate ligands to form transient cell adhesion. They are rod-like proteins with a long extracellular part of variable length ending with the lectin domain, which is a C-type lectin that binds carbohydrates only in the presence of calcium ions. Three major types of selectins are identified based on their tissue specificity and length – L-selectins, P-selectins, and E-selectins.
Selectins in Immune Response
The endothelial cells lining the blood vessels express P-selectins and store them in the vesicular bodies called Weible-Palade bodies. During inflammation, histamine stimulation rapidly mobilizes these vesicles to the cell surface. These activated endothelial cells also upregulate their E-selectin and P-selectin genes, thus priming them to recruit free-flowing leukocytes from the bloodstream.
Leukocytes, such as neutrophils and eosinophils, express the carbohydrate ligands, such as PSGL-1, on their cell surface. The long selectins protruding from the endothelial cells can easily interact with these ligands and "catch" the free-flowing leukocytes from the bloodstream. Selectins are initially in the closed conformation, and therefore bind weakly to their ligands. However, as the leukocyte flows along, the shear stress of these interactions triggers the selectins to open. Selectins in open conformation can bind strongly to their ligands and thus, help slow down the leukocytes.
Selectins in Cancer
Metastatic cancer cells hijack the normal selectin-mediated recruitment process to invade healthy tissues. These metastatic cells express the carbohydrate ligands on their cell surface and thus become receptive to bind the endothelial cells. Upon binding, the cancer cells can escape the blood vessel, through a process called extravasation. The cancerous cells can then infiltrate the new site, producing secondary tumors.
Suggested Reading
- Borsig, Lubor. "Selectins in cancer immunity." Glycobiology 28.9 (2018): 648-655.
- Gout, Stéphanie, Pierre-Luc Tremblay, and Jacques Huot. "Selectins and selectin ligands in extravasation of cancer cells and organ selectivity of metastasis." Clinical & experimental metastasis 25.4 (2008): 335-344.