Biological functions of phosphatidylinositol transfer proteins

2004 ◽  
Vol 82 (1) ◽  
pp. 254-262 ◽  
Author(s):  
Sheri M Routt ◽  
Vytas A Bankaitis
Keyword(s):  
Lipid Metabolism ◽  
Protein Secretion ◽  
Plant Development ◽  
Membrane Trafficking ◽  
Biological Functions ◽  
Cellular Functions ◽  
Transfer Protein ◽  
Phosphatidylinositol Transfer ◽  
Available Information ◽  
Phosphatidylinositol Transfer Proteins

Phosphatidylinositol/phosphatidylcholine transfer proteins (PITPs) are ubiquitous and highly conserved proteins that are believed to regulate lipid-mediated signaling events. Their ubiquity and conservation notwithstanding, PITPs remain remarkably uninvestigated. Little is known about the coupling of specific PITPs to explicit cellular functions or the mechanisms by which PITPs interface with apppropriate cellular functions. The available information indicates a role for these proteins in regulating the interface between lipid metabolism and membrane trafficking in yeast, signaling in plant development, the trafficking of specialized luminal cargo in mammalian enterocytes, and neurological function in mammals. Herein, we review recent advances in PITP biology and discuss as yet unresolved issues in this field.Key words: phosphatidylinositol transfer protein, secretion, lipid signaling, phosphoinositide.

Loss Of Phosphatidylinositol Transfer Proteins (PITPs) Causes Thrombocytopenia Due To a Defect In Thrombopoiesis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2313-2313
Author(s):  
Aae Suzuki ◽  
Liang Zhao ◽  
Yuhuan Wang ◽  
Lurong Lian ◽  
Sang H. Min ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Conflicts Of Interest ◽  
Total Phospholipid ◽  
Phospholipid Content ◽  
Wild Type ◽  
Double Knockout ◽  
In Vitro Synthesis ◽  
Platelet Counts ◽  
Phosphatidylinositol Transfer ◽  
Phosphatidylinositol Transfer Proteins

Abstract Phosphatidylinositol (PI) comprises less than one percent of the total phospholipid content in platelets. However, PI serves important roles in second messenger signaling and membrane trafficking. The inositol head groups of PI can be phosphorylated by PI kinases to generate seven different phosphoinositides (PtdIns), each capable of producing unique signaling events. The biogenesis of these PtdIns is restricted to various organelle compartments, and PtdIns cannot diffuse freely within the aqueous cytosol. Therefore, the synthesis of phosphoinositides is tightly regulated in space as well as in time. Class I phosphatidylinositol transfer proteins (PITPs) facilitate the exchange of PtdIns between different membrane compartments by shuttling these phospholipids across the aqueous cytoplasm. Two PITP isoforms (α and β) are expressed in platelets. We have generated a mouse model in which these isoforms are deleted in megakaryocytes and in platelet lineages by using a CRE/Lox strategy. Mice lacking either of the PITP isoforms (PITPαfl/fl PF4 Cre+ or PITPβfl/fl PF4 Cre +) or mice lacking both of the isoforms of PITP (PITPαfl/fl PITPβfl/fl PF4 Cre+) in their platelets and in their megakaryocytes appeared normal, and exhibited no evidence of spontaneous hemorrhage. Mice lacking individual isoforms of PITP exhibited mild thrombocytopenia, while mice lacking both PITP isoforms in their platelets and in their megakaryocytes had platelet counts that were 45% ± 4% less than the platelet counts of their matched littermate controls. These knockout mice had no splenomegaly, and the double knockout platelets had a normal lifespan when infused into wild type recipient mice. Together, these findings suggest that the loss of PITPα and PITPβ in platelets and in megakaryocytes causes thrombocytopenia due to decreased platelet production. Analysis of the megakaryocytes in PITPαfl/fl PITPβfl/fl PF4 Cre+ mice demonstrates that the relative number of megakaryocytes within their bone marrow was unaffected by the loss of both PITP isoforms (control 1.04 ± 0.12% versus knockout 0.98 ± 0.07%). These knockout megakaryocytes also expressed proplatelets in tissue culture as efficiently (44 ± 7% of megakaryocytes had a least one proplatelet) as wild type megakaryocytes (40.9 ± 2.9%). These data suggest that the thrombocytopenia in PITPαfl/fl PITPβfl/fl PF4 Cre+ mice is due to a failure of their megakaryocyte proplatelet extensions to release platelets into the circulation. It is notable that we have also found that the deletion of either PITPα or PITPβ leads to decreased in vitro synthesis of phosphoinositides, such as PI(4)P and PI(4,5)P2, and second messengers, such as IP3. Together, these data indicate that PITPα and PITPβ in megakaryocytes are critical for normal proplatelet release. We speculate that this is due to the loss of specific phosphoinositides required during thrombopoiesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Sec14-like phosphatidylinositol transfer proteins Sec14l3/SEC14L2 act as GTPase proteins to mediate Wnt/Ca2+ signaling

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Bo Gong ◽  
Weimin Shen ◽  
Wanghua Xiao ◽  
Yaping Meng ◽  
Anming Meng ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Calcium Release ◽  
Tissue Formation ◽  
Transfer Protein ◽  
Phosphatidylinositol Transfer ◽  
Biochemical Analyses ◽  
Canonical Wnt ◽  
Phosphatidylinositol Transfer Proteins ◽  
G Protein Coupled ◽  
Hydrolysis Of

The non-canonical Wnt/Ca2+ signaling pathway plays important roles in embryonic development, tissue formation and diseases. However, it is unclear how the Wnt ligand-stimulated, G protein-coupled receptor Frizzled activates phospholipases for calcium release. Here, we report that the zebrafish/human phosphatidylinositol transfer protein Sec14l3/SEC14L2 act as GTPase proteins to transduce Wnt signals from Frizzled to phospholipase C (PLC). Depletion of sec14l3 attenuates Wnt/Ca2+ responsive activity and causes convergent and extension (CE) defects in zebrafish embryos. Biochemical analyses in mammalian cells indicate that Sec14l3-GDP forms complex with Frizzled and Dishevelled; Wnt ligand binding of Frizzled induces translocation of Sec14l3 to the plasma membrane; and then Sec14l3-GTP binds to and activates phospholipase Cδ4a (Plcδ4a); subsequently, Plcδ4a initiates phosphatidylinositol-4,5-bisphosphate (PIP2) signaling, ultimately stimulating calcium release. Furthermore, Plcδ4a can act as a GTPase-activating protein to accelerate the hydrolysis of Sec14l3-bound GTP to GDP. Our data provide a new insight into GTPase protein-coupled Wnt/Ca2+ signaling transduction.

scholarly journals Identification of a Novel Family of Nonclassic Yeast Phosphatidylinositol Transfer Proteins Whose Function Modulates Phospholipase D Activity and Sec14p-independent Cell Growth

2000 ◽  
Vol 11 (6) ◽  
pp. 1989-2005 ◽  
Author(s):  
Xinmin Li ◽  
Sheri M. Routt ◽  
Zhigang Xie ◽  
Xiaoxia Cui ◽  
Min Fang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Phospholipase D ◽  
Sequence Similarity ◽  
Primary Sequence ◽  
Transfer Protein ◽  
Sequence Identity ◽  
Phosphatidylinositol Transfer ◽  
Phosphatidylinositol Transfer Proteins

Yeast phosphatidylinositol transfer protein (Sec14p) is essential for Golgi function and cell viability. We now report a characterization of five yeast SFH (Sec Fourteen Homologue) proteins that share 24–65% primary sequence identity with Sec14p. We show that Sfh1p, which shares 64% primary sequence identity with Sec14p, is nonfunctional as a Sec14p in vivo or in vitro. Yet,SFH proteins sharing low primary sequence similarity with Sec14p (i.e., Sfh2p, Sfh3p, Sfh4p, and Sfh5p) represent novel phosphatidylinositol transfer proteins (PITPs) that exhibit phosphatidylinositol- but not phosphatidylcholine-transfer activity in vitro. Moreover, increased expression of Sfh2p, Sfh4p, or Sfh5p rescues sec14-associated growth and secretory defects in a phospholipase D (PLD)-sensitive manner. Several independent lines of evidence further demonstrate thatSFH PITPs are collectively required for efficient activation of PLD in vegetative cells. These include a collective requirement for SFH proteins in Sec14p-independent cell growth and in optimal activation of PLD in Sec14p-deficient cells. Consistent with these findings, Sfh2p colocalizes with PLD in endosomal compartments. The data indicate that SFH gene products cooperate with “bypass-Sec14p” mutations and PLD in a complex interaction through which yeast can adapt to loss of the essential function of Sec14p. These findings expand the physiological repertoire of PITP function in yeast and provide the first in vivo demonstration of a role for specific PITPs in stimulating activation of PLD.

The Diverse Biological Functions of Phosphatidylinositol Transfer Proteins in Eukaryotes

2006 ◽  
Vol 41 (1) ◽  
pp. 21-49 ◽  
Author(s):  
Scott E. Phillips ◽  
Patrick Vincent ◽  
Kellie E. Rizzieri ◽  
Gabriel Schaaf ◽  
Vytas A. Bankaitis ◽  
...  
Keyword(s):  
Biological Functions ◽  
Phosphatidylinositol Transfer ◽  
Phosphatidylinositol Transfer Proteins

scholarly journals Phosphatidylinositol transfer protein β displays minimal sphingomyelin transfer activity and is not required for biosynthesis and trafficking of sphingomyelin

2002 ◽  
Vol 366 (1) ◽  
pp. 23-34 ◽  
Author(s):  
Bruno SÉGUI ◽  
Victoria ALLEN-BAUME ◽  
Shamshad COCKCROFT
Keyword(s):  
Intracellular Trafficking ◽  
Lipid Transfer ◽  
Transfer Protein ◽  
Golgi Membranes ◽  
Bound Lipids ◽  
Cellular Lipids ◽  
Phosphatidylinositol Transfer ◽  
Phosphatidylinositol Transfer Proteins

Mammalian phosphatidylinositol transfer proteins (PITPs) α and β, which share 77% identity, have been shown to exhibit distinct lipid-transfer activities. In addition to transferring phosphatidylinositol (PI) and phosphatidylcholine (PC), PITPβ has been shown to transfer sphingomyelin (SM), and this has led to the suggestion that PITPβ is important for the regulation of SM metabolism. In the present study, we have analysed the ability of human PITPβ to transfer and regulate the metabolism of cellular SM. We report that, in vitro, the two PITP isoforms were comparable in mediating PI, PC or SM transfer. Using permeabilized HL-60 cells as the donor compartment, both PITP isoforms efficiently transferred PI and PC, and were slightly active towards SM, with the activity of PITPβ being slightly greater. To identify which cellular lipids were selected by PITPs, PITPα and PITPβ were exposed to permeabilized HL-60 cells, and subsequently repurified and analysed for their bound lipids. Both PITPs were able to select only PI and PC, but not SM. SM synthesis takes place at the Golgi, and PITPβ was shown to localize in that compartment. To examine the role of PITPβ in SM biosynthesis, Golgi membranes were used. Purified Golgi membranes had lost their endogenous PITPβ, but were able to recruit PITPβ when added exogenously. However, PITPβ did not enhance the activities of either SM synthase or glucosylceramide synthase. Further analysis in COS-7 cells overexpressing PITPβ showed no effects on (a) SM and glucosylceramide biosynthesis, (b) diacylglycerol or ceramide levels, (c) SM transport from the Golgi to the plasma membrane, or (d) resynthesis of SM after exogenous sphingomyelinase treatment. Altogether, these observations do not support the suggestion that PITPβ participates in the transfer of SM, the regulation of SM biosynthesis or its intracellular trafficking.

Lipid metabolism in phosphatidylinositol transfer protein α-deficient vibrator mice

2004 ◽  
Vol 317 (2) ◽  
pp. 444-450 ◽  
Author(s):  
Marie E Monaco ◽  
James Kim ◽  
WeiFeng Ruan ◽  
Rosemary Wieczorek ◽  
David L Kleinberg ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Transfer Protein ◽  
Phosphatidylinositol Transfer Protein ◽  
Phosphatidylinositol Transfer

scholarly journals Neural stem cell interkinetic nuclear migration is controlled by a phosphatidylinositol transfer protein/non-canonical planar cell polarity signaling axis

2020 ◽  
Author(s):  
Zhigang Xie ◽  
Vytas A. Bankaitis
Keyword(s):  
Cell Polarity ◽  
Membrane Trafficking ◽  
Planar Cell Polarity ◽  
Critical Role ◽  
Nuclear Migration ◽  
Transfer Protein ◽  
Interkinetic Nuclear Migration ◽  
Phosphatidylinositol Transfer Protein ◽  
Signaling Axis ◽  
Phosphatidylinositol Transfer

The mammalian neocortex undergoes explosive expansion during embryonic development. From an evolutionary perspective, higher complexity of the neocortex is accompanied by a prominent expansion in its lateral dimension so that the neocortical surface area is increased. Expansion in the radial dimension throughout evolution is limited so that neocortical thickness is strongly restricted1–3. The underlying mechanisms for restricting neocortical thickness remain unclear. Expansion of the developing mouse neocortex is driven by neurogenesis which is itself primarily fueled by neural stem cells (NSCs). NSCs form a pseudostratified epithelium and exhibit a hallmark cell cycle-dependent nuclear movement termed interkinetic nuclear migration (IKNM) 2–4. While IKNM plays a critical role in cell fate determination, it remains a poorly understood process. Herein, we demonstrate IKNM relies on a phosphatidylinositol transfer protein (PITP)-noncanonical planar cell polarity (ncPCP) signaling axis that restricts radial expansion of the developing neocortex. Ablation of PITPα/PITPβ in NSCs compromised IKNM -- resulting in a thickened neocortex and perturbed curvature of its ventricular surface. Those phenotypic derangements in IKNM and neocortical morphogenesis were recapitulated in mouse embryos individually ablated for two ncPCP receptor gene activities and in a mosaic neocortex expressing a dominant-negative variant of a third ncPCP receptor. Finally, PITP signaling links to ncPCP pathway activity by promoting membrane trafficking of a subset of ncPCP receptors from the trans-Golgi network to the NSC cell surface. We conclude IKNM is a driving force for a special form of convergent extension regulated by coupling PITP-mediated phosphoinositide signaling with activity of the evolutionarily conserved ncPCP pathway.

Sign in / Sign up

Export Citation Format

Share Document