Platelets lacking PIP5KIγ have normal integrin activation but impaired cytoskeletal-membrane integrity and adhesion.
Three isoforms of phosphatidylinositol-4-phosphate 5-kinase (PIP5KIα, PIP5KIβ, and PIP5KIγ) can each catalyze the final step in the synthesis of phosphatidylinositol-4,5-bisphosphate (PIP2), which in turn can be either converted to second messengers or bind directly to and thereby regulate proteins such as talin. A widely quoted model speculates that only p90, a longer splice form of platelet-specific PIP5KIγ, but not the shorter p87 PIP5KIγ, regulates the ligand-binding activity of integrins via talin. However, when we used mice genetically engineered to lack only p90 PIP5KIγ, we found that p90 PIP5KIγ is not critical for integrin activation or platelet adhesion on collagen. However, p90 PIP5KIγ-null platelets do have impaired anchoring of their integrins to the underlying cytoskeleton. Platelets lacking both the p90 and p87 PIP5KIγ isoforms had normal integrin activation and actin dynamics, but impaired anchoring of their integrins to the cytoskeleton. Most importantly, they formed weak shear-resistant adhesions ex vivo and unstable vascular occlusions in vivo. Together, our studies demonstrate that, although PIP5KIγ is essential for normal platelet function, individual isoforms of PIP5KIγ fulfill unique roles for the integrin-dependent integrity of the membrane cytoskeleton and for the stabilization of platelet adhesion.
Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Yanfeng
Y
Wang
Liang
L
Zhao
Aae
A
Suzuki
Lurong
L
Lian
Sang H
SH
Min
Ziqian
Z
Wang
Rustem I
RI
Litvinov
Timothy J
TJ
Stalker
Tadayuki
T
Yago
Arkadiusz G
AG
Klopocki
David W
DW
Schmidtke
Helen
H
Yin
John K
JK
Choi
Rodger P
RP
McEver
John W
JW
Weisel
John H
JH
Hartwig
Charles S
CS
Abrams
D008841:Actin Cytoskeleton / Q000502:physiology; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D001792:Blood Platelets / Q000166:cytology* / Q000201:enzymology*; D003599:Cytoskeleton / Q000502:physiology; D005091:Exons / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D016023:Integrins / Q000378:metabolism*; D007536:Isomerism; D008533:Megakaryocytes / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052898:Optical Tweezers; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D010973:Platelet Adhesiveness / Q000502:physiology*; D011247:Pregnancy; D016608:Talin / Q000378:metabolism; D013927:Thrombosis / Q000201:enzymology* / Q000235:genetics
D016023:Integrins; D016608:Talin; C496077:Tln1 protein, mouse; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase