A Balance of Opposing Signals within the Cytoplasmic Tail Controls the Lysosomal Targeting of P-selectin

Blagoveshchenskaya, Anastasia; Hewitt, Eric W.; Cutler, Daniel F.

doi:10.1074/jbc.273.43.27896

Cited by 23 publications

(27 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…P-selectin internalizes into a transferrinpositive endosome (Blagoveshchenskaya et al, 1998bArribas and Cutler 2000;Straley and Green, 2000) before further processing leads either to its recycling to the TGN (Arribas and Cutler 2000;Straley and Green, 2000) or to delivery to the lysosome (Green et al, 1994;Blagoveshchenskaya et al, 1998aBlagoveshchenskaya et al, , 1998bBlagoveshchenskaya et al, , 2000aArribas and Cutler 2000). We found that internalized anti-P-selectin accumulates in an SNX17-positive endosome that is TfnR-positive and that may also accumulate M6PR.…”

Section: Snx17 Retards the Degradation Of P-selectinmentioning

confidence: 76%

“…We have shown in HEK-293 cells that this does indeed occur. It is important to point out that a great deal is known about the endocytic trafficking of P-selectin in heterologous systems (Green et al, 1994;Setiadi et al, 1995;Norcott et al, 1996;Blagoveshchenskaya et al, 1998aBlagoveshchenskaya et al, , 1998bBlagoveshchenskaya et al, , 1999Blagoveshchenskaya et al, , 2002Strasser et al, 1999;Blagoveshchenskaya and Cutler, 2000a;Straley and Green, 2000;Daugherty et al, 2001;Kaur and Cutler, 2002), and we are confident that an analysis of P-SNX17 Modulates P-selectin Trafficking selectin trafficking through the endocytic pathway in HEK-293 cells will not differ significantly from, e.g., that in PC12, H.Ep.2, CHO or most importantly HUVECs. We therefore believe that SNX17 will be involved in physiological control of the endocytic sorting of P-selectin, as indicated by controlling the amount of HRP-P-selectin reaching the lysosome where degradation occurs.…”

Section: Effect Of Snx17 On Physiological Functioning Of P-selectinmentioning

confidence: 99%

“…We have determined whether SNX17 overexpression modulates Pselectin degradation in HEK-293 cells. Because HEK-293 cells lack a storage compartment, newly synthesized Pselectin will be delivered to the plasma membrane (Disdier et al, 1992;Green et al, 1994;Blagoveshchenskaya et al, 1998a;Straley et al, 1998). It will then internalize and be delivered to lysosomes or recycle via the TGN, to enter a new round of exo-and endocytosis.…”

Section: Snx17 Retards the Degradation Of P-selectinmentioning

confidence: 99%

“…The leukocyte receptor P-selectin is an extreme example of this because is it only present at the plasma membrane of endothelial cells for a few minutes early in the inflammatory response (Hattori et al, 1989;McEver et al, 1989). Uncontrolled surface appearance of P-selectin would lead to chronic leukocyte recruitment, but its rapid internalization (Blagoveshchenskaya et al, 1998a;Setiadi et al, 1995) and subsequent endocytic trafficking (Subramaniam et al, 1993;Arribas and Cutler, 2000;Straley and Green, 2000) is such as to preclude its uncontrolled return to the plasma membrane.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Sorting Nexin 17 Accelerates Internalization Yet Retards Degradation of P-selectin

Williams

Schlüter

Roberts

et al. 2004

MBoC

Self Cite

View full text Add to dashboard Cite

The transient appearance of P-selectin on the surface of endothelial cells helps recruit leukocytes into sites of inflammation. The tight control of cell surface P-selectin on these cells depends on regulated exocytosis of WeibelPalade bodies where the protein is stored and on its rapid endocytosis. After endocytosis, P-selectin is either sorted via endosomes and the Golgi apparatus for storage in Weibel-Palade bodies or targeted to lysosomes for degradation. A potential player in this complex endocytic itinerary is SNX17, a member of the sorting nexin family, which has been shown in a yeast two-hybrid assay to bind P-selectin. Here, we show that overexpression of SNX17 in mammalian cells can influence two key steps in the endocytic trafficking of P-selectin. First, it promotes the endocytosis of P-selectin from the plasma membrane. Second, it inhibits the movement of P-selectin into lysosomes, thereby reducing its degradation.

show abstract

Section: Snx17 Retards the Degradation Of P-selectinmentioning

confidence: 76%

Section: Effect Of Snx17 On Physiological Functioning Of P-selectinmentioning

confidence: 99%

Section: Snx17 Retards the Degradation Of P-selectinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sorting Nexin 17 Accelerates Internalization Yet Retards Degradation of P-selectin

Williams

Schlüter

Roberts

et al. 2004

MBoC

Self Cite

View full text Add to dashboard Cite

show abstract

“…This might be by posttranslational modification. Phosphorylation of P-selectin has been reported [40][41][42] as has S-acylation 43 (reportedly influencing association with tetraspanin microdomains for other proteins 24 ). Alternatively, because internalization of CD63 can be controlled by an association with syntenin, 44 or L6, 45 this in turn may control the trafficking of P-selectin together with CD63.…”

Section: Discussionmentioning

confidence: 99%

CD63 is an essential cofactor to leukocyte recruitment by endothelial P-selectin

Doyle

Ridger

Ferraro

et al. 2011

Blood

Self Cite

View full text Add to dashboard Cite

The activation of endothelial cells is critical to initiating an inflammatory response. Activation induces the fusion of WeibelPalade Bodies (WPB) with the plasma membrane, thus transferring P-selectin and VWF to the cell surface, where they act in the recruitment of leukocytes and platelets, respectively. CD63 has long been an established component of WPB, but the functional significance of its presence within an organelle that acts in inflammation and hemostasis was unknown. We find that ablating CD63 expression leads to a loss of P-selectindependent function: CD63-deficient HUVECs fail to recruit leukocytes, CD63-deficient mice exhibit a significant reduction in both leukocyte rolling and recruitment and we show a failure of leukocyte extravasation in a peritonitis model. Loss of CD63 has a similar phenotype to loss of P-selectin itself, thus CD63 is an essential cofactor to P-selectin. (Blood. 2011; 118(15):4265-4273) IntroductionEndothelial cells contain specialized regulated secretory organelles, Weibel-Palade bodies (WPB), 1 which play an important role in inflammation and hemostasis. The best-known components of WPB are the major cargo protein von Willebrand Factor (VWF), 2 P-selectin, 3 and CD63. 4 On WPB fusion the VWF tubules unfurl into long platelet-catching strings at a site of injury, 5 playing a major role in hemostasis. VWF also has an important function in inflammation, because activated platelets make a major contribution to the inflammatory response. 6 Further, VWF binds the leukocyte receptor PSGL-1 and integrin ␣ M ␤ 2 7 implicating a more direct role in leukocyte recruitment to the endothelium.The integral membrane protein leukocyte receptor P-selectin is stored within the membrane of WPB of endothelial cells 3,8 from where it is delivered to the cell surface within minutes after secretagogue-triggered exocytosis. 9 P-selectin plays a key early role in the inflammatory trafficking of leukocytes, being the first receptor involved in recruiting leukocytes from flowing plasma to the endothelial surface. 10,11 CD63 12 is the third long-established component of WPB, 4 but this protein has no identified endothelial-specific function in either hemostasis or inflammation. This universally expressed membrane protein of the tetraspanin family is best known as a marker of the intralumenal vesicles within multivesicular endosomes. The phenotype of CD63 knockout mice suggests a redundant role for CD63 in development and distribution of immune system cells, very mild effects on platelet adhesion, and a role in kidney physiology. 13 It has been reported that CD63 might modulate the trafficking of other membrane proteins, including altering internalization from the plasma membrane, and most recently, in targeting synaptotagmin VII to the lysosome, thus facilitating lysosome-plasma membrane fusion. 12,14 Whether CD63 is involved in the hemostatic or inflammatory roles of WPB is unknown, but if so, it might operate by modulating trafficking events that underpin WPB formation and function. CD63 is found only...

show abstract

In silico determination of intracellular glycosylation and phosphorylation sites in human selectins: Implications for biological function

Ahmad

Hoessli²,

Gupta

et al. 2007

J of Cellular Biochemistry

View full text Add to dashboard Cite

Post-translational modifications provide the proteins with the possibility to perform functions in addition to those determined by their primary sequence. However, analysis of multifunctional protein structures in the environment of cells and body fluids is made especially difficult by the presence of other interacting proteins. Bioinformatics tools are therefore helpful to predict protein multifunctionality through the identification of serine and threonine residues wherein the hydroxyl group is likely to become modified by phosphorylation or glycosylation. Moreover, serines and threonines where both modifications are likely to occur can also be predicted (YinYang sites), to suggest further functional versatility. Structural modifications of hydroxyl groups of P-, E-, and L-selectins have been predicted and possible functions resulting from such modifications are proposed. Functional changes of the three selectins are based on the assumption that transitory and reversible protein modifications by phosphate and O-GlcNAc cause specific conformational changes and generate binding sites for other proteins. The computer-assisted prediction of glycosylation and phosphorylation sites in selectins should be helpful to assess the contribution of dynamic protein modifications in selectin-mediated inflammatory responses and cell-cell adhesion processes that are difficult to determine experimentally.

show abstract

A Balance of Opposing Signals within the Cytoplasmic Tail Controls the Lysosomal Targeting of P-selectin

Cited by 23 publications

References 56 publications

Sorting Nexin 17 Accelerates Internalization Yet Retards Degradation of P-selectin

Sorting Nexin 17 Accelerates Internalization Yet Retards Degradation of P-selectin

CD63 is an essential cofactor to leukocyte recruitment by endothelial P-selectin

In silico determination of intracellular glycosylation and phosphorylation sites in human selectins: Implications for biological function

Contact Info

Product

Resources

About