Outside-in signaling through class I PI3Ks. Class I PI3Kβ is particularly important for thrombus stability, and is activated downstream of α_IIbβ₃ via a pathway involving the kinases Src, Syk, and Pyk2. This leads to phosphorylation of the E3-protein ubiquitin ligase c-Cbl, which associates with the p85 regulatory subunit of class I PI3K. Activated class I PI3Ks phosphorylate membrane PtdIns(4,5)P₂ to form PtdIns(3,4,5)P₃, which leads to the recruitment and/or activation of a range of PtdIns(3,4,5)P₃-binding proteins. These include kinases such as BTK/Tec, PDK1, and AKT. PtdIns(3,4,5)P₃ can also regulate a range of GAPs and GEFs for small GTPases, including RASA3, dedicator of cytokinesis (DOCK) proteins, and Cytohesin-family members. Syk may also associate directly with the β₃-integrin C-terminal tail. Hashed lines represent phosphorylation events; yellow circles represent activating phosphorylation; orange circles represent inhibitory phosphorylation.