Session Title: T cell Biology and Targets in Autoimmune Disease Poster II
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Crk proteins are a family of adaptors that play an important role in regulating multiple T cell functions. The two main Crk isoforms are CrkII and CrkL that are encoded by separate genes. Similar to other adaptors, they bind to phosphorylated tyrosine motifs of many proteins via their SH2 domain to recruit additional effectors utilizing their SH3 domain. One of these effectors is C3G, a guanine nucleotide exchange factor regulating Rap1 activation and subsequent adhesion. T cells adhere to multiple cells including endothelial cells and antigen presenting cells (APC). The interphase between T cell and APC is known as the immunological synapse (IS). It is made of multiple T cell receptors that interact with adhesion molecules and ligands presented on the surface of the APC. The distribution of these molecules is characterized by a specific organization that can be divided into central supermolecular activation clusters (cSMACs) and peripheral SMAC (pSMAC).
The goal of this study was to uncover the mechanism by which Crk proteins regulate Rap1 activation within the IS of primary human T cells using lipid bilayer and TIRFm microscopy.
We determined that activation of T cells trough the antigen receptor led to polarization of activated Rap1 toward the IS. Unlike other GTPases, Rap1 was excluded from the cSMAC. Notably, C3G was recruited to the same compartments as Rap1. Although both CrkII and CrkL populated both compartments of the IS, their distribution was phosphorylation dependent. While phosphorylated (and inactive) CrkII was limited to the cSMAC, CrkL phosphorylation resulted in pSMAC distribution. Subsequent biochemical and genetic studies confirmed that signaling initiated by the antigen receptor resulted in CrkII dephosphorylation that was mediated by the phosphatase SHP2.
In summary, we discover a new signaling pathway where signals downstream the T cell receptor result in recruitment of SHP2 to dephosphorylate and activate the adaptor CrkII. Activated CrkII travel to pSMAC where it recruits C3G, leading to Rap1 activation and LFA-1 mediated adhesion.
To cite this abstract in AMA style:Mor A, Alfaguter I. The Adaptor Protein Crkii Regulates Rap1 Activation in the Immunological Synapse [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/the-adaptor-protein-crkii-regulates-rap1-activation-in-the-immunological-synapse/. Accessed September 20, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-adaptor-protein-crkii-regulates-rap1-activation-in-the-immunological-synapse/