Pathways implicated in CD28 signaling. Cross-linking of CD28 induces tyrosine phosphorylation of the cytoplasmic tail, allowing interaction with Grb2 and PI3K (although both are portrayed interacting with a single CD28 dimer, it is unknown whether this is a physiological complex). Grb2 links via SLP-76 to the Rho family guanine-nucleotide exchange factor Vav, connecting CD28 to activation of Rac and CDC42. PI3K can signal by recruiting Akt. Negative regulation of Vav by Cbl-b and of Akt by PP2A opposes CD28 costimulatory signals.