血小板利用由I类磷脂鞘氮醇转运蛋白（PITP）生成的信号转导途径。两种哺乳动物的I类PITP，PITPα和PITPβ，是单个PITP结构域可溶蛋白，由不同基因编码并具有77％的序列同源性，但它们在哺乳动物生物学中的各自作用尚未被表征。这些蛋白被认为在不同的细胞内膜区间之间穿梭磷脂鞘氮醇和磷脂酰胆碱，从而调节磷脂酰肌醇合成和第二信使形成。我们先前发现，血小板特异性删除主要表达的小鼠PITP亚型PITPα对止血无影响，但影响肿瘤转移形成并破坏了磷脂酰肌醇信号传导。在这里，我们发现在血小板中缺乏PITPβ的小鼠呈现出类似的表型。然而，与具有受损脂质转移活性的PITPα缺失血小板裂解物不同，PITPβ缺失血小板裂解物具有基本正常的脂质转移活性，尽管两种亚型都对体外磷脂酰肌醇合成做出贡献。此外，我们发现血小板特异性删除两种PITP会导致体外血小板聚集/分泌和扩散缺陷，后者对尾部出血和严重的肿瘤传播都产生了影响。我们的研究还表明，PITP亚型对维持内源性磷脂酰肌醇PI（4,5）P2水平和激动剂刺激的第二信使形成至关重要。这里展示的数据表明，两种I类PITP亚型都对血小板中的磷脂酰肌醇信号传导有贡献，可能通过不同的生化机制或在不同的亚细胞区域中发挥作用。它们的功能重叠，任何单个亚型均能维护血小板的稳态。Copyright © 2023美国血液学会。

Platelets utilize signal transduction pathways facilitated by Class I phosphatidylinositol transfer proteins (PITPs). The two mammalian Class I PITPs, PITPα and PITPβ, are single PITP domain soluble proteins that are encoded by different genes and have 77% sequence identity, though their individual roles in mammalian biology remain uncharacterized. These proteins are believed to shuttle phosphatidylinositol and phosphatidylcholine between separate intracellular membrane compartments, thereby regulating phosphoinositide synthesis and second messenger formation. Previously, we observed that platelet-specific deletion of PITPα, the predominant expressed murine PITP isoform, had no effect on hemostasis, but had impaired tumor metastasis formation and disrupted phosphoinositide signaling. Here, we find that mice lacking the lesser expressed PITPβ in their platelets exhibit a similar phenotype. However, in contrast to PITPα-null platelet lysates that have impaired lipid transfer activity, PITPβ-null platelet lysates have essentially normal lipid transfer activity, although both isoforms contribute to phosphoinositide synthesis in vitro. Moreover, we found that platelet-specific deletion of both PITPs leads to ex vivo platelet aggregation/secretion and spreading defects, impaired tail bleeding, and profound tumor dissemination. Our studies also demonstrate that PITP isoforms are required for maintaining endogenous phosphoinositide PI(4,5)P2 levels and agonist stimulated second messenger formation. The data shown here demonstrate that both class I PITP isoforms contribute to phosphoinositide signaling in platelets, likely through distinct biochemical mechanisms or in different subcellular domains. They are functionally overlapping and either single isoform is able to maintain the homeostasis of platelets.Copyright © 2023 American Society of Hematology.