Interaction of Shc with the ζ Chain of the T Cell Receptor Upon T Cell Activation

Abstract

The shc oncogene product is tyrosine-phosphorylated by Src family kinases and after its phosphorylation interacts with the adapter protein Grb2 (growth factor receptor-bound protein 2). In turn, Grb2 interacts with the guanine nucleotide exchange factor for Ras, mSOS. Because several Src family kinases participate in T cell activation and Shc functions upstream of Ras, the role of Shc in T cell signaling was examined. Shc was phosphorylated on tyrosine after activation through the T cell receptor (TCR), and subsequently interacted with Grb2 and mSOS. The Src homology region 2 (SH2) domain of Shc directly interacted with the tyrosine-phosphorylated zeta chain of the TCR. Thus, Shc may couple TCR activation to the Ras signaling pathway.

Stimulation through the T cell receptor leads to interactions between SHB and several signaling proteins

“…As a consequence of this, the pattern of Jurkat cell tyrosine phosphorylation in response to TCR activation is dramatically altered. There has been a signi®cant recent controversy about the potential role of Grb2 versus Shc in linking the z chain to Sos and the Ras pathway (Ravichandran et al, 1993;Osman et al, 1995). It is possible that potential di erences in these studies partly derive from the participation of Shb.…”

“…The ITAMs are repeated sequences of YXXL separated by 6 ± 8 amino acids and their tyrosine phosphorylation generates binding sites for Src homology 2 (SH2) domains of signaling molecules, such as those of ZAP 70 (Chan et al, 1992;Hutchcroft et al, 1992). This initiates a cascade of reactions involving the adaptor protein p36/38 (Weber et al, 1992;Gilliland et al, 1992;Sieh et al, 1994), Lnk (Huang et al, 1995), Grb2 (Ravichandran et al, 1993) and the signaling pathways of phospholipase C g, PI-3 kinase and MAP kinase (Ravichandran et al, 1993;Secrist et al, 1991;Thompson et al, 1992). Eventually, a signal is propagated which induces altered gene transcription, IL-2 production, di erentiation and a modi®cation of the balance between cell proliferation and apoptosis (Weiss and Littman, 1994;Perlmutter et al, 1993).…”

Constitutive activation of the Ras/MAP kinase pathway and enhanced TCR signaling by targeting the Shc adaptor to membrane rafts

“…However, there is evidence that phosphorylation at tyrosines 239 and 240 may also contribute to Ras activation, possibly as a result of a cooperation of both Grb-2 binding sites in stabilizing Sos in a membraneproximal localization (Harmer and DeFranco, 1997). In T-cells, Shc is phosphorylated on tyrosine residues following TCR triggering, and in that state not only binds Grb-2/Sos complexes, but furthermore enhances the association between Grb-2 and Sos (Ravichandran et al, 1993(Ravichandran et al, , 1995Baldari et al, 1995). Recruitment of Shc to the activated TCR is achieved through a dual interaction with z chain-bound ZAP-70 through the PTB domain (Milia et al, 1996), and with the z chain itself through the SH2 domain (Ravichandran et al, 1993), potentially resulting in enhanced stability of Shc/Grb-2/Sos complexes at the activated TCR.…”

Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells

“…Shc proteins are tyrosine-phosphorylated following activation of receptor tyrosine kinases (van der Geer et al, 1994), including the epidermal growth factor receptor (EGFR) , platelet-derived growth factor receptor (PDGFR) (Yokote et al, 1994), nerve growth factor receptor (TrkA) (Obermeier et al, 1994), insulin receptor (Pronk et al, 1993) and erbB-2 (Segatto et al, 1993) as well as receptors that lack intrinsic tyrosine kinase activity such as the T-cell receptor (TCR) (Ravichandran et al, 1993), B-cell receptor (Saxton et al, 1994), receptors for the interleukins (Burns et al, 1993;Cutler et al, 1993;Ravichandran and Burako , 1994) and the erythropoietin receptor . Additionally, tyrosine phosphorylation of Shc has been detected after activation of G-protein coupled receptors (Cazubon et al, 1994;Ptaznik et al, 1995;Touhara et al, 1995;van Biesen et al, 1995;Chen et al, 1996), ligation of integrins (Maniero et al, 1995;Wary et al, 1996) and in cells expressing activated Src, Fps, Sea or Lck (McGlade et al, 1992a;Crowe et al, 1994;Baldari et al, 1995;Pelicci et al, 1995a), implicating Shc as an important substrate of cytoplasmic tyrosine kinases.…”

“…The Shc PTB domain has been shown to bind directly to N-P-X-pY sequence motifs in the cytoplasmic domains of the EGFR (Blaikie et al, 1994), TrkA (Dikic et al, 1995), RET (Lorenzo et al, 1997) and the IL-2Rb chain (Ravichandran et al, 1996). The Shc SH2 domain preferentially binds to tyrosine phosphorylated peptides in the sequence context pY-E/I-X-I/L/M (where X represents any amino acid) (Songyang et al, 1994) and has been proposed to mediate the binding of Shc to the PDGFR (Yokote et al, 1994), EGFR , RET (Lorenzo et al, 1997), and the CD3 zeta chain of the T-cell receptor (Ravichandran et al, 1993). While interactions between the Shc SH2 domain and several membrane receptors have been demonstrated, the physiologic importance of these interac-tions is less clear, since the PTB domain appears to be predominant in mediating the interaction of SHC with activated growth factor receptors.…”