Abl tyrosine kinases in T-cell signaling

Abstract

Stimulation of the T-cell antigen receptor (TCR) leads to the activation of signaling pathways that are essential for T-cell development and the response of mature T cells to antigens. The TCR has no intrinsic catalytic activity, but TCR engagement results in tyrosine phosphorylation of downstream targets by non-receptor tyrosine kinases. Three families of tyrosine kinases have long been recognized to play critical roles in TCR-dependent signaling. They are the Src, zeta-associated protein of 70 kDa, and Tec families of kinases. More recently, the Abelson (Abl) tyrosine kinases have been shown to be activated by TCR engagement and to be required for maximal TCR signaling. Using T-cell conditional knockout mice deficient for Abl family kinases, Abl (Abl1) and Abl-related gene (Arg) (Abl2), it was recently shown that loss of Abl kinases results in defective T-cell development and a partial block in the transition to the CD4(+)CD8(+) stage. Abl/Arg double null T cells exhibit impaired TCR-induced signaling, proliferation, and cytokine production. Moreover, conditional knockout mice lacking Abl and Arg in T cells exhibit impaired CD8(+) T-cell expansion in vivo upon Listeria monocytogenes infection. Thus, Abl kinase signaling is required for both T-cell development and mature T-cell function.

Fig. 1. Abl kinases are activated in response to TCR engagement and regulate downstream signaling events

Abl kinases are activated in response to TCR stimulation in a pathway that requires Lck kinase activity. The activated Abl kinases promote the phosphorylation of ZAP-70 and LAT leading to activation of IL-2 transcription. Abl kinases also regulate actin polymerization through the Abi/Wave complex and HS1. The Wave complex promotes actin polymerization downstream of activated Rac leading to Arp2/3-mediated actin polymerization. The role of Abi and Wave phosphorylation by Abl is unclear. HS1 is also phosphorylated by Abl and regulates F-actin stabilization.

Fig. 2. Multiple cell surface receptors promote Abl kinase activation and signaling

Abl kinases are activated by ligand-stimulated receptor tyrosine kinases (RTKs), adhesion receptors such as integrins and cadherins, and immunoreceptors such as the BCR and TCR. The activated Abl kinases signal to modulate cell proliferation, survival, or cytoskeletal processes in multiple cells types.

Fig. 3. Structural domains of Abl and Arg

The Abl and Arg kinases are highly homologous in their SH3, SH2, and SH1 (kinase) domains in the N-terminal half. The C-terminus contains proline-rich (PXXP) motifs that recruit SH3-containing proteins. Both Abl and Arg have a C-terminal calponin-homology F-actin binding domain. Arg also has an internal talin-like F-actin binding domain and a microtubule binding domain. Abl has a DNA binding domain, three nuclear localization sequences (NLS), and one nuclear export sequence (NES). A G-actin binding domain is present in Abl just upstream of the C-terminal F-actin binding domain.

Fig. 4. Abl kinases regulate TCR-mediated integrin activation and adhesion

Abl kinases interact with the Wave protein complex and regulate Rap1 activation via CrkL-C3G resulting in inside-out integrin activation and adhesion. Wave also regulates TCR-mediated integrin clustering and high affinity binding through the recruitment of a complex containing Arp2/3, vinculin, and talin.