Tyrosine phosphorylation–mediated regulation of SFK activity. SFK activity is regulated through the phosphorylation of conserved tyrosine residues in the C-terminal tail and activation loop. Phosphorylation of the C-terminal tyrosine residue inhibits SFK activity by mediating formation of an intramolecular interaction with the SH2 domain that blocks the active site. A second intramolecular interaction between the SH3 domain and the proline-rich SH2-kinase linker region maintains the SFK in an inactive conformation. Dephosphorylation of the C-terminal tyrosine residue by the protein-tyrosine phosphatases CD148, PTP-1B, and possibly Shp1, releases the intramolecular interactions and actives the SFK. Maximal activation is achieved through trans-autophosphorylation of the activation loop tyrosine residue. Phosphorylation of the C-terminal inhibitory tyrosine residue by Csk or Csk homologous kinase (Chk) re-establishes the SH2 C-terminal inhibitory phosphotyrosine interaction and returns the SFK to an inactive conformation. Dephosphorylation of the activation loop tyrosine returns the SFK to a basally active state. CD148 may be responsible for dephosphorylating this site in platelets.