Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytes.
Phosphatidylserine (PS) exposure is normally associated with apoptosis and the removal of dying cells. We observed that PS is exposed constitutively at high levels on T lymphocytes that express low levels of the transmembrane tyrosine phosphatase CD45RB. CD45 was shown to be a negative regulator of PS translocation in response to various signals, including activation of the ATP receptor P2X(7). Changes in PS distribution were shown to modulate several membrane activities: Ca(2+) and Na(+) uptake through the P2X(7) cation channel itself; P2X(7)-stimulated shedding of the homing receptor CD62L; and reversal of activity of the multidrug transporter P-glycoprotein. The data identify a role for PS distribution changes in signal transduction, rapidly modulating the activities of several membrane proteins. This seems to be an all-or-none effect, coordinating the activity of most or all the molecules of a target protein in each cell. The data also suggest a new approach to circumventing multidrug resistance.
Elliott
James I
JI
MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. james.elliott@csc.mrc.ac.uk
Surprenant
Annmarie
A
Marelli-Berg
Federica M
FM
Cooper
Joanne C
JC
Cassady-Cain
Robin L
RL
Wooding
Carol
C
Linton
Kenneth
K
Alexander
Denis R
DR
Higgins
Christopher F
CF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001692:Biological Transport / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019041:L-Selectin / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D017239:Paclitaxel / Q000493:pharmacokinetics; D010718:Phosphatidylserines / Q000378:metabolism*; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017304:Annexin A5; D007473:Ion Channels; D008565:Membrane Proteins; C546469:P2rx7 protein, mouse; D010718:Phosphatidylserines; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D019041:L-Selectin; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D017493:Leukocyte Common Antigens; D017239:Paclitaxel; D002118:Calcium