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First published online February 21, 2007
doi: 10.1242/10.1242/jcs.000786

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T-cell-receptor-dependent actin regulatory mechanisms

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, 816D Abramson Research Center, 3615 Civic Center Blvd., Philadelphia, PA 19104, USA

View larger version (32K): [in this window] [in a new window]   Fig. 1. Actin regulatory pathways during T-cell activation by antigen-presenting cells. The drawing shows the formation of the immunological synapse (IS) at the T-cell–APC interface, and the distal pole complex (DPC) at the opposite face of the T cell. Both complexes are organized in part by actin filaments. TCR stimulation recruits the actin regulators WASp/WIP, WAVE2 and HS1 to the IS, and pathways involving specific kinases, adapter molecules and Rho GTPases activate Arp2/3-complex-dependent polymerization of branched actin filaments. In parallel, engagement of the co-stimulatory molecules CD2 and CD28 induces dephosphorylation and activation of cofilin. The severing activity of cofilin disassembles filaments to monomers and generates new barbed ends for filament elongation, a process that further enhances actin polymerization at the IS. TCR stimulation also induces transient dephosphorylation of the ERM proteins ezrin and moesin, leading to the release of these proteins from actin filaments and plasma membrane binding proteins. Subsequent rephosphorylation of ERM proteins is coupled by unknown mechanisms to their movement away from the site of TCR engagement. This process allows ERM proteins to attach to their cargo molecules (which include both cell surface and cytoplasmic proteins), near the IS and then sweep these molecules rearward to form the DPC.

View larger version (44K): [in this window] [in a new window]   Fig. 2. Domain structures of actin regulatory proteins important for T-cell activation. Binding partners are shown below the domain with which they associate. Sites of phosphorylation that have been implicated in regulating protein function are indicated. Regions with sequence and functional similarity are similarly colored. Note, for example, that WASp and WAVE proteins share a conserved VCA domain responsible for binding actin monomers and the Arp2/3 complex. This domain consists of three subdomains: the WASp-homology 2 (WH2)/verprolin region, a cofilin homology region and an acidic region. HS1 contains only the acidic subdomain within its N-terminal acidic region (NTA), whereas WIP contains two copies of the WH2/verprolin subdomain. Note also the prevalence of proline-rich regions (Pro) among actin regulatory proteins at the IS; these regions are responsible for numerous interactions with SH3-domain-containing proteins involved in T-cell signaling. WH1, WASp homology domain 1; GBD, GTPase binding domain; WHD, WAVE homology domain; BR, basic region; HTH, helix-turn-helix (cortactin) repeat region; CC, coiled-coil region; SH3, Src homology 3 domain; ADF, actin depolymerizing factor/cofilin; FERM, Band 4.1, ezrin, radixin moesin homology domain.