Model of CD2–CD58 microdomain-mediated signaling. Uniformly diffused molecules in plasma membrane of T cells (left) are spatially organized upon CD2–CD58 interaction (middle and right). CD2–CD58 interaction generates microdomains mediated by intermolecular interaction between CD2 extracellular domains. Cytoplasmic domains of CD2 within highly concentrated microdomains, particularly poly proline regions, can activate Lck by competitively binding to autoinhibitory SH3 domain in Lck (inactive, closed form). The active, open form of Lck molecules can trans-autophosphorylate other Lck molecules at tyrosine 394, resulting in further enhancement of Lck kinase activity. The membrane-anchored phosphatase CD45 is excluded from CD2 microdomains, which prevents Lck deactivation through CD45-mediated dephosphorylation of tyrosine 394. CD45 outside of the microdomains plays a role in dephosphorylating phosphotyrosine (P) 505 in Lck, which inhibits kinase activity via interaction with autoinhibitory SH2 domain. A subset of Lck, opened by CD45 dephosphorylation at Y505, can then diffuse into CD2 microdomains, leading to further activation. Active Lck molecules in microdomains can phosphorylate ITAM domains in TCR and facilitate subsequent downstream signaling involving LAT and other molecules. Although not shown, similar models may apply to the activation of related Src-like kinases such as Fyn. Although microdomains act to concentrate proteins, these molecular interactions are dynamic, and proteins can diffuse into and dissociate from these domains, as shown previously (Douglass and Vale, 2005).