The Role of Crk Adaptor Proteins in T-Cell Adhesion and Migration - PubMed

Figure 2

Involvement of Crk adaptor proteins in TCR- and integrin-coupled signaling pathways that regulate T-lymphocyte adhesion. A simplified scheme of surface receptors and signaling pathways that regulate T-cell activation and adhesion. T-cell receptor (TCR) ligation results in Lck-mediated tyrosine phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on the intracellular portion of the CD3 subunits, leading to the recruitment of ζ-chain-associated protein kinase of 70 kDa (ZAP-70) and its phosphorylation on several distinct tyrosine residues, including Tyr315 (13). The subsequent Lck- and ZAP-70-mediated tyrosine phosphorylation of multiple substrates activates several signaling cascades, in which calcineurin (CaN) and protein kinase C theta (PKCθ) play a major role, leading to cell activation, proliferation, and differentiation. In parallel, Crk adaptor proteins transiently interact via their SH2 domain with ZAP-70 Tyr315 and, apparently, promote the recruitment of additional Crk-binding proteins to the receptor site that contribute to the “outside-in” signaling pathway (11). Crk interaction with the guanine nucleotide-exchange factor (GEF), C3G, imposes the conversion of the small GTPase, RAP1, to an active GTP-bound protein, which in turn leads to activation of the LFA-1 integrin and increases T-cell adhesion. Activation of this “inside-out” signaling pathway, which promotes integrin-mediated T-cell adhesion, is sensitive to a regulation by immunophilins (14). GEF-mediated activation of Rap1, which is essential for upregulation of the integrin receptors, can also be mediated by a WASP family verprolin-homologous protein-2 (WAVE2)-regulated CrkL-C3G complexes (15) as well as by other Crk-independent pathways (16). Integrins can also initiate “outside-in” and “inside-out” signaling pathways since their interaction with ICAM-1 or extracellular matrix results in signal delivery that promotes conformational changes in adjacent integrins leading to increase in their clustering and binding affinity. For simplicity, additional effector proteins that interact with Crk, such as WAVE and immunophilins, which are also involved in the regulation of T-cell adhesion, are not included in the figure. Red arrows indicate direct effects and black arrows indicate indirect effects. Ag, antigen; AP-1, activation protein-1; C3G, CRK SH3 domain-binding guanine nucleotide-releasing factor; CaN, calcineurin; Cas, Crk-associated substrate; CasL, Cas lymphocyte type; Crk, CT10 (chicken tumor virus number 10) regulator of kinase; GDP, guanosine diphosphate; GTP, guanosine-5′-triphosphate; Lck, lymphocyte-specific protein tyrosine kinase; NF-AT, nuclear factor of activated T cells; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; P, a site of tyrosine phosphorylation; PKCθ, protein kinase C theta; PLCγ1, phospholipase C gamma 1; Rac, Ras-related C3 botulinum toxin substrate; Rap, Ras-related protein; Ras, rat sarcoma; ZAP-70, zeta-chain-associated protein kinase 70.