PMID- 20851766 OWN - NLM STAT- MEDLINE DCOM- 20110208 LR - 20101018 IS - 1873-3913 (Electronic) IS - 0898-6568 (Linking) VI - 23 IP - 1 DP - 2011 Jan TI - RhoH modulates pre-TCR and TCR signalling by regulating LCK. PG - 249-58 LID - 10.1016/j.cellsig.2010.09.009 [doi] AB - Pre-T-cell receptor (pre-TCR) and TCR signals govern the development of T-lymphocytes. RhoH, a hematopoietic-specific and GTPase-deficient member of the RhoGTPase family, is required in the development of T-lymphocytes. Here we found that RhoH binds and modulates LCK, the non-receptor tyrosine kinase crucial in initiating pre-TCR and TCR signallings. In both pre-TCR and TCR signalling transduction, LCK is phosphorylated by CSK to maintain the inactive state of LCK at rest. Upon being activated, CSK phosphorylation is removed and LCK autophosphorylation leads to LCK activation and further phosphorylates ZAP70 to initiate further downstream signalling. At rest, LCK may be recruited to the plasma membrane by RhoH, which also binds CSK, resulting in LCK inactivation. Additionally, the presence of RhoH enhances the inactivation phosphorylation of LCK by CSK. RhoH was found to bind preferentially inactive LCK, indicating that, upon ligand-mediated TCR activation, LCK is dephosphorylated resulting in LCK autoactivation and its release from RhoH. Thus RhoH is a critical part of the microenvironment for maintaining the inactive state of LCK. Furthermore, we found that the reduction of RhoH levels results in LCK autoactivation and constitutive activation of the TCR pathway. Our findings indicate that RhoH is a key adapter protein that maintains LCK in the inactive state, contributing to the regulation of both pre-TCR and TCR signalling during T-cell development. The data also supports a model for ligand-independent signal transduction by pre-TCR. CI - Copyright (c) 2010 Elsevier Inc. All rights reserved. FAU - Wang, Hong AU - Wang H AD - Division of Hematology and Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. howang@rci.rutgers.edu FAU - Zeng, Xin AU - Zeng X FAU - Fan, Zhigang AU - Fan Z FAU - Lim, Bing AU - Lim B LA - eng GR - 5R01DK047636/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20100916 PL - England TA - Cell Signal JT - Cellular signalling JID - 8904683 RN - 0 (Membrane Glycoproteins) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (Receptors, Antigen, T-Cell, alpha-beta) RN - 0 (RhoH protein, human) RN - 0 (Transcription Factors) RN - 0 (pre-T cell receptor alpha) RN - EC 2.7.10.2 (Lymphocyte Specific Protein Tyrosine Kinase p56(lck)) RN - EC 3.6.5.2 (rho GTP-Binding Proteins) SB - IM MH - Cell Line MH - Humans MH - Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/*metabolism MH - Membrane Glycoproteins/*metabolism MH - Receptors, Antigen, T-Cell/*metabolism MH - Receptors, Antigen, T-Cell, alpha-beta/*metabolism MH - Signal Transduction MH - T-Lymphocytes/enzymology/*immunology MH - Transcription Factors/*metabolism MH - rho GTP-Binding Proteins/*metabolism EDAT- 2010/09/21 06:00 MHDA- 2011/02/09 06:00 CRDT- 2010/09/21 06:00 PHST- 2010/08/17 00:00 [received] PHST- 2010/09/06 00:00 [accepted] PHST- 2010/09/21 06:00 [entrez] PHST- 2010/09/21 06:00 [pubmed] PHST- 2011/02/09 06:00 [medline] AID - S0898-6568(10)00265-2 [pii] AID - 10.1016/j.cellsig.2010.09.009 [doi] PST - ppublish SO - Cell Signal. 2011 Jan;23(1):249-58. doi: 10.1016/j.cellsig.2010.09.009. Epub 2010 Sep 16.