A Nck-Pak1 signaling module is required for T-cell receptor-mediated activation of NFAT, but not of JNK - PubMed (original) (raw)
A Nck-Pak1 signaling module is required for T-cell receptor-mediated activation of NFAT, but not of JNK
D Yablonski et al. EMBO J. 1998.
Abstract
The T-cell antigen receptor (TCR) triggers a signaling cascade initiated by the tyrosine kinase Lck and requiring the proto-oncogene p95(vav). Vav is activated by Lck and can function as a guanine nucleotide exchange factor for the Rho-family GTPases, Rac1 and Cdc42. To investigate the involvement of these GTPases in TCR signaling, we focused on their well characterized effector, Pak1. This serine/threonine kinase is activated by GTP-bound Rac1 or Cdc42. However, its role in mediating downstream signaling events is controversial. We observed rapid, TCR-dependent activation of Pak1 and TCR-inducible association of Pak1 with Nck, which was tyrosine phosphorylated following stimulation. Pak1 activation occurred independently of Ras activation or calcium flux, but was dependent on the Lck tyrosine kinase, and was downstream of Vav and Cdc42. Dominant negative Pak1 or Nck specifically inhibited TCR-mediated activation of the nuclear factor of activated T cells (NFAT) transcription factor. TCR-mediated activation of Erk2 was also inhibited by dominant negative Pak. However, Pak1 activation was neither necessary nor sufficient for TCR-dependent c-Jun N-terminal kinase (JNK) activation. Therefore, Pak1 acts downstream of Vav and is required for activation of Erk2 and NFAT by a JNK-independent pathway. This is the first demonstration of a requirement for Pak to mediate the regulation of gene expression by an extracellular ligand.
Similar articles
- A PAK1-PIX-PKL complex is activated by the T-cell receptor independent of Nck, Slp-76 and LAT.
Ku GM, Yablonski D, Manser E, Lim L, Weiss A. Ku GM, et al. EMBO J. 2001 Feb 1;20(3):457-65. doi: 10.1093/emboj/20.3.457. EMBO J. 2001. PMID: 11157752 Free PMC article. - TCR and CD28 are coupled via ZAP-70 to the activation of the Vav/Rac-1-/PAK-1/p38 MAPK signaling pathway.
Salojin KV, Zhang J, Delovitch TL. Salojin KV, et al. J Immunol. 1999 Jul 15;163(2):844-53. J Immunol. 1999. PMID: 10395678 - Vav-Rac1-mediated activation of the c-Jun N-terminal kinase/c-Jun/AP-1 pathway plays a major role in stimulation of the distal NFAT site in the interleukin-2 gene promoter.
Kaminuma O, Deckert M, Elly C, Liu YC, Altman A. Kaminuma O, et al. Mol Cell Biol. 2001 May;21(9):3126-36. doi: 10.1128/MCB.21.9.3126-3136.2001. Mol Cell Biol. 2001. PMID: 11287617 Free PMC article. - TAOK3, a Regulator of LCK-SHP-1 Crosstalk during TCR Signaling.
Ormonde JVS, Nie Y, Madrenas J. Ormonde JVS, et al. Crit Rev Immunol. 2019;39(1):59-81. doi: 10.1615/CritRevImmunol.2019030480. Crit Rev Immunol. 2019. PMID: 31679194 Review. - Vav1: a key signal transducer downstream of the TCR.
Tybulewicz VL, Ardouin L, Prisco A, Reynolds LF. Tybulewicz VL, et al. Immunol Rev. 2003 Apr;192:42-52. doi: 10.1034/j.1600-065x.2003.00032.x. Immunol Rev. 2003. PMID: 12670394 Review.
Cited by
- LAT-independent Erk activation via Bam32-PLC-γ1-Pak1 complexes: GTPase-independent Pak1 activation.
Rouquette-Jazdanian AK, Sommers CL, Kortum RL, Morrison DK, Samelson LE. Rouquette-Jazdanian AK, et al. Mol Cell. 2012 Oct 26;48(2):298-312. doi: 10.1016/j.molcel.2012.08.011. Epub 2012 Sep 13. Mol Cell. 2012. PMID: 22981863 Free PMC article. - Pak2 is required for actin cytoskeleton remodeling, TCR signaling, and normal thymocyte development and maturation.
Phee H, Au-Yeung BB, Pryshchep O, O'Hagan KL, Fairbairn SG, Radu M, Kosoff R, Mollenauer M, Cheng D, Chernoff J, Weiss A. Phee H, et al. Elife. 2014 May 13;3:e02270. doi: 10.7554/eLife.02270. Elife. 2014. PMID: 24843022 Free PMC article. - HIV-1 Activates T Cell Signaling Independently of Antigen to Drive Viral Spread.
Len ACL, Starling S, Shivkumar M, Jolly C. Len ACL, et al. Cell Rep. 2017 Jan 24;18(4):1062-1074. doi: 10.1016/j.celrep.2016.12.057. Cell Rep. 2017. PMID: 28122231 Free PMC article. - Nck adapter proteins: functional versatility in T cells.
Lettau M, Pieper J, Janssen O. Lettau M, et al. Cell Commun Signal. 2009 Feb 2;7:1. doi: 10.1186/1478-811X-7-1. Cell Commun Signal. 2009. PMID: 19187548 Free PMC article. - A Pak- and Pix-dependent branch of the SDF-1alpha signalling pathway mediates T cell chemotaxis across restrictive barriers.
Volinsky N, Gantman A, Yablonski D. Volinsky N, et al. Biochem J. 2006 Jul 1;397(1):213-22. doi: 10.1042/BJ20051655. Biochem J. 2006. PMID: 16515536 Free PMC article.
References
- Crit Rev Oncog. 1996;7(1-2):65-88 - PubMed
- Cell. 1997 May 2;89(3):457-67 - PubMed
- J Biol Chem. 1996 Oct 18;271(42):25746-9 - PubMed
- Curr Opin Cell Biol. 1996 Apr;8(2):216-22 - PubMed
- Curr Opin Cell Biol. 1997 Apr;9(2):205-12 - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous