The Shc adaptor protein, particularly its p52 isoform, has been identified as a primary signaling partner for the tyrosine(s)-phosphorylated cytoplasmic tails of activatedβ3integrins. Inspired by our recent structure of the Shc PTB domain in complex with a bi-phosphorylated peptide derived fromβ3cytoplasmic tail, we have initiated the investigation of Shc interaction with phospholipids of the membrane. We are particularly focused on PtdIns and their effects on Shc mediated integrin signalingin vitro. Here we present thermodynamic profiles and molecular details of the interactions between Shc, integrin, and PtdIns, all of which have been studied by ITC and solution NMR methods. A model of p52 Shc interaction with phosphorylatedβ3integrin cytoplasmic tail at the cytosolic face of the plasma membrane is proposed based on these data.