Simplified endothelial signaling cascades in response to leukocyte attachment. Adhesion of leukocytes through multiple transmembrane proteins such as ICAM-1, VCAM-1, and CD47 promotes activation of small GTPases (depicted as Rac1, RhoA, and RhoG) and PTK signaling, such as activation of Src and Pyk2. PTK activity leads to phosphorylation of actin binding proteins (e.g., cortactin) and focal adhesion components (FAK, paxillin, and Cas) that together with filamin promote ICAM-1 clustering and actin remodeling that is required for the formation of the adhesion cup. PTKs also promote the phosphorylation of VE-cadherin, which together with VCAM-1-mediated dissociation of VE-PTP from VE-cadherin leads to junctional hyperphosphorylation. At the same time, SHP2 mediates VE-cadherin dephosphorylation specifically at tyrosine 731. VE-cadherin endocytosis may follow. Src-mediated phosphorylation of PECAM-1 is required from PECAM-1 translocation from the LBRC to the plasma membrane.