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

Plyte, Simon; Majolini, M. Bernardetta; Pacini, Sonia; Scarpini, Francesca; Bianchini, Claretta; Lanfrancone, Luisa; Pelicci, PierGiuseppe; Baldari, Cosima T.

doi:10.1038/sj.onc.1203451

Cited by 49 publications

(53 citation statements)

References 40 publications

(50 reference statements)

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“…In murine T cells, where CD38-mediated LAT tyrosine phosphorylation is weaker than in Jurkat T cells, we favor a model in which the adaptor Shc might have a crucial role (31). In this sense, Shc partitions into rafts following TCR engagement (14), and targeting of Shc to rafts leads to constitutive activation of the Ras/Erk signaling pathway and enhanced TCR signaling (73).…”

Section: Discussionmentioning

confidence: 95%

CD38 Signaling in T Cells Is Initiated within a Subset of Membrane Rafts Containing Lck and the CD3-ζ Subunit of the T Cell Antigen Receptor

Muñoz

Navarro

Pavón

et al. 2003

Journal of Biological Chemistry

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In this study we present data supporting that most CD38 is pre-assembled in a subset of Brij 98-resistant raft vesicles, which were stable at 37°C, and have relatively high levels of Lck and the CD3-subunit of T cell antigen receptor-CD3 complex in contrast with a Brij 98-soluble pool, where CD38 is associated with CD3-, and Lck is not detected. Our data further indicate that following CD38 engagement, LAT and Lck are tyrosinephosphorylated exclusively in Brij 98-resistant rafts, and some key signaling components translocate into rafts (i.e. Sos and p85-phosphatidylinositol 3-kinase). Moreover, N-Ras results activated within rafts immediately upon CD38 ligation, whereas activated Erk was mainly found in soluble fractions with delayed kinetics respective to Ras activation. Furthermore, full phosphorylation of CD3-and CD3-⑀ only occurs in rafts, whereas partial CD3-tyrosine phosphorylation occurs exclusively in the soluble pool, which correlated with increased levels of c-Cbl tyrosine phosphorylation in the non-raft fractions. Taken together, these results suggest that, unlike the non-raft pool, CD38 in rafts is able to initiate and propagate several activating signaling pathways, possibly by facilitating critical associations within other raft subsets, for example, LAT rafts via its capacity to interact with Lck and CD3-. Overall, these findings provide the first evidence that CD38 operates in two functionally distinct microdomains of the plasma membrane.

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Section: Discussionmentioning

confidence: 95%

CD38 Signaling in T Cells Is Initiated within a Subset of Membrane Rafts Containing Lck and the CD3-ζ Subunit of the T Cell Antigen Receptor

Muñoz

Navarro

Pavón

et al. 2003

Journal of Biological Chemistry

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“…Cholesterol rich microdomains or lipid rafts have been proposed to function as molecular platforms for signal transduction where speci®c proteins are recruited into the appropriate environment for successful signaling interactions (Simons and Ikonen, 1997). Given that many signaling proteins including Ras, tyrosine and serine kinases and phosphatases are dierentially localized between raft and non-raft microdomains (Cary and Cooper, 2000;Couet et al, 1997;Kurzchalia and Parton, 1999;Liu et al, 1996Liu et al, , 1997Okamoto et al, 1998;Plyte et al, 2000;Roy et al, 1999), it is not unreasonable to speculate that Raf-1 initially recruited by H-Ras to cholesterol rich lipid rafts may need to access other non-raft domains for ecient activation. If so, the results presented here showing that serine-threonine phosphatase inhibition has a less dramatic eect on K-Ras than H-Ras-dependent Raf-1 activation (Figure 1a, b) could re¯ect dierences in microlocalization of these Ras isoforms (Prior et al, 2001;Roy et al, 1999) From the data presented in this study and our previous results we propose the following sequence for Raf-1 activation (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions

2001

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Raf-1 activation is a complex process which involves plasma membrane recruitment, phosphorylation, proteinprotein and lipid-protein interactions. We now show that PP1 and PP2A serine-threonine phosphatases also have a positive role in Ras dependent Raf-1 activation. General serine-threonine phosphatase inhibitors such sodium¯uoride, or û-glycerophosphate and sodium pyrophosphate, or speci®c PP1 and PP2A inhibitors including microcystin-LR, protein phosphatase 2A inhibitor I 1 or protein phosphatase inhibitor 2 all abrogate H-Ras and K-Ras dependent Raf-1 activation in vitro. A critical Raf-1 target residue for PP1 and PP2A is S259. Serine phosphatase inhibitors block the dephosphorylation of S259, which accompanies Raf-1 activation, and Ras dependent activation of mutant Raf259A is relatively resistant to serine phosphatase inhibitors. Sucrose gradient analysis demonstrates that serine phosphatase inhibition increases the total amount of 14-3-3 and Raf-1 associated with the plasma membrane and signi®cantly alters the distribution of 14-3-3 and Raf-1 across dierent plasma membrane microdomains. These observations suggest that dephosphorylation of S259 is a critical early step in Ras dependent Raf-1 activation which facilitates 14-3-3 displacement. Inhibition of PP1 and PP2A therefore causes plasma membrane accumulation of Raf-1/14-3-3 complexes which cannot be activated. Oncogene (2001) 20, 3949 ± 3958.

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“…It was originally suggested, mostly on the basis of in vitro studies, that isoprenyl modifications may result in exclusion from cholesterol-rich structures (37) and liquid ordered domains (38). However, further work has supported the view that prenylated proteins, especially Ha-Ras, are sensitive to alterations in the cholesterol content of plasma membranes and associate with lipid rafts (20,39). However, only a fraction of Ha-Ras appears to be recruited to lipid rafts and the fraction of Ha-Ras that localizes in rafts appears to decrease upon GTP binding (40).…”

Section: Figmentioning

confidence: 99%

Agonist-dependent Traffic of Raft-associated Ras and Raf-1 Is Required for Activation of the Mitogen-activated Protein Kinase Cascade

Rizzo¹,

Kraft²,

Watkins³

et al. 2001

Journal of Biological Chemistry

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

Cited by 49 publications

References 40 publications

CD38 Signaling in T Cells Is Initiated within a Subset of Membrane Rafts Containing Lck and the CD3-ζ Subunit of the T Cell Antigen Receptor

CD38 Signaling in T Cells Is Initiated within a Subset of Membrane Rafts Containing Lck and the CD3-ζ Subunit of the T Cell Antigen Receptor

Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions

Agonist-dependent Traffic of Raft-associated Ras and Raf-1 Is Required for Activation of the Mitogen-activated Protein Kinase Cascade

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