Role of adapter molecules in TCR coupling to p21ras

In a variety of cell types many receptors regulate p21ras by stimulating the guanine nucleotide exchange protein SOS, which is associated with the adapter protein GRB-2 (Figure 2). GRB-2 is composed of two SH3 domains that bind to a guanine nucleotide exchange protein that activates p21r"% and an SH2 domain that interacts with tyrosine phosphoproteins that regulate cell localization/ function of this p21 ""-exchange protein. In T cells, at least two tyrosine phosphoproteins can potentially interact with GRB-2 SH2 domains, namely SHC and the membrane-located tyrosine phosphoprotein p36, which may be related to the Lnk protein recently cloned from rat lymph node. Indeed, the major tyrosine phosphoprotein to associate with GRB-2 SH2 domains in TCR-activated cells is a 36 kDa molecule (p36). In TCR-activated T cells, both SHC and p36

are tyrosine phosphorylated and in vitro can be shown to bind GRB-2 SH2 domains. SHC has an SH2 domain that can bind to the tyrosine phosphorylated TCR f chain, hence tyrosine phosphorylated SHC could potentially recruit GRB-2 and SOS to the TCR complex in activated cells. However, reports disagree about the formation of SHC-GRB-2-SOS complexes after TCR ligation, having only been demonstrated in murine T cell hybridomas but not TCR-activated peripheral blood derived T cells. This illustrates that there may be considerable heterogeneity of TCR responses in different cell types. In addition, it appears that the SHC interaction with TCR £ chains is of relatively low affinity as compared with the binding of tyrosine kinases such as ZAP-70 or p59/v". This may ensure that SHC interaction with f is transient and only sufficient to bring SHC to the TCR complex where it can be tyrosine phosphorylated, but is insufficient for the formation of stable TCR-SHC complexes. The formation of p36-GRB-2-SOS complexes is a rapid response to TCR ligation that correlates well with p21r',s regulation. The failure to find tyrosine-phosphorylated SHC binding to GRB-2 and SOS in TCR-activated cells may be due to competition between p36 and SHC for the SH2 domain of GRB-2.

In addition to GRB-2, it is clear that there are several other adapter molecules that may be involved in coupling the TCR to the p21r,,s pathway. For instance, T cells express another protein termed C3G which can catalyze guanine nucleotide exchange on p21r"s and which binds to the SH3 domains of the adapter molecule CRK. Three forms of CRK are found in T cells and CRK has a single SH2 domain and one or two SH3 domains. TCR triggering results in tyrosine phosphorylation of CRK-binding proteins such as a Cbl, analogous to the TCR regulation of GRB-2 binding complexes. A constitutively active Cbl mutant has been demonstrated to stimulate Ras-dependent and calcium-stimulated activation of NFAT. In fact, there is evidence that GRB-2 is constitutively associated with Cbl regardless of the activation of Jurkat cells. Another report has demonstrated that TCR ligation stimulates tyrosine phosphorylation of Cbl which correlates with the dissociation of the GRB-2-CbI complex and the formation of CRK-Cbl complexes via the CRK SH2 domain. The reasons for the redundancy in the coupling of the TCR to p21r"s remain unclear. One possibility is that these multiple mechanisms provide several contingency routes in the event of malfunction of one or more of these mechanisms. A leading alternative hypothesis is that subtle differences exist in the pathways downstream of Ras.

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