The adaptor protein Crk in immune response

Abstract

The adaptor proteins Crk (CT10 (chicken tumor virus number 10) regulator of kinase), including CrkI, CrkII and Crk-like, are important signal molecules that regulate a variety of cellular processes. Considerable progress has been made in understanding the roles of the Crk family proteins in signal transduction, with a focus on cellular transformation and differentiation. However, since Crk was identified in 1988, very few studies have addressed how Crk regulates the immune response. Recent work demonstrates that Crk proteins function as critical signal molecules in regulating immune cell functions. Emerging data on the roles of Crk in activation and inhibitory immunoreceptor signaling suggest that Crk proteins are potential immunotherapeutic targets in cancer and infectious diseases. The aim of this review is to summarize recent key findings regarding the role of Crk in immune responses mediated by T, B and natural killer (NK) cells. In particular, the roles of Crk in NK cell functions are discussed.

Figure 1. Comparison of CrkI and CrkII in sequence

CrkI and CrkII sequences are aligned by Multalin version 5.4.1 software (http://multalin.toulouse.inra.fr/multalin/). The consensus sequences are marked in Red.

Figure 2. Domains of Crk and its binding partners

Schematic diagram of the domains of CrkL (303 aa) and CrkII (304 aa). The binding partners of SH2 and SH3 domains are listed on the top.

Figure 3. Domain Comparison of CrkL and CrkII

Sequence alignment of CrkL and CrkII by Multalin version 5.4.1 (http://multalin.toulouse.inra.fr/multalin/). The consensus symbols are as follows: ! is anyone of IV. % is anyone of FY. # is anyone of NDQEBZ. NES = nuclear export signal. PRR = proline-rich region.

Figure 4. Signaling mediated by Crk in human NK cell

Phosphorylation of Crk induced by inhibitory receptors blocks NK cell activation. At activating synapses, Crk is required for the movement of activation receptor microclusters and their ability to trigger activation signals (not shown). During inhibition triggered by inhibitory receptor, Crk is phosphorylated and associates with the tyrosine kinase c-Abl. Interconversion between un-phosphorylated Crk (Green) and phosphorylated Crk (Red) functions as a molecular switch in the control of NK cell activation via interaction between Crk and pVav-1 or interaction between pCrk and SHP-1. Green indicates receptors and signal molecules that contribute to activation. Red indicates receptors and signal molecules that contribute to inhibition.