getic barriers, similar to recent models for the role of lateral mechanical forces in integrin activation (Zhu et al., 2008).
The specific adapters that link TCR to F-actin are not well described. The complex may include NCK, SLP-76, ADAP, SKAP55, EVL, Vav, Rac, Cdc42 and WASP certainly may play a role once signaling is initiated (Barda-Saad et al., 2005; Bubeck Wardenburg et al., 1998; Krause et al., 2000). It has also been suggested that ZAP-70 may play a role through binding of ezrin (Ilani et al., 2007). It appears that TCR signaling in microclusters ceases when the microcluster reaches the actin depleted cSMAC. Since activated TCR appear equipped to generate their own dynamic actin focus, the suppression of this mode of actin dymanics in the cSMAC is likely to be active, rather than a passive dissipation of lamellar actin. Less is known about the basal interactions of TCR with actin that might be available to stabilize a cluster early in the triggering process. This is likely a complex situation. An example of the potential complexity can be seen in interaction networks recently compiled as the integrin adhesome (Zaidel-Bar et al., 2007).
Once the ITAMs are exposed Src family kinases can then initiate phosphorylation by diffusion into the same domain (Douglass and Vale, 2005)(Fig 2). Exclusion of CD45 in the nascent foci would increase the half-life of the phosphorylated ITAM allowing sufficient time for ZAP-70 recruitment (Varma et al., 2006). This cluster may interact more strongly with LAT so that ZAP-70 could phosphorylate LAT and Itk to initiate PLC-g recruitment and initiation of Ca2+ signaling, PKC activation and Ras-GRP recruitment. Integrin microclusters will be interspersed with the TCR microclusters. Integrin dependent signaling will generate additional diacylglycerol for RasGRP by activating phospholipase D and phosphatidic acid phosphatase (Mor et al., 2007). Electron micrographs of membrane sheets suggest that immunoreceptor rich and LAT rich islands only partially mix (Lillemeier et al., 2006;