ArticleMolecular and cellular biology2004
Regulation of the Src family kinase Lck by Hsp90 and ubiquitination.
Article in Molecular and cellular biology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 56 citations in OpenAlex.
- Targeting proteostasis pathways for cancer therapy.Journal of pharmaceutical analysis · 2025Review
- TRPA1 activation and Hsp90 inhibition synergistically downregulate macrophage activation and inflammatory responses in vitro.BMC immunology · 2023Article
- The LCK-14-3-3ζ-TRPM8 axis regulates TRPM8 function/assembly and promotes pancreatic cancer malignancy.Cell death & disease · 2022Article
- The Activity and Stability of p56Lck and TCR Signaling Do Not Depend on the Co-Chaperone Cdc37.International journal of molecular sciences · 2020Article
- Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy.Cancers · 2019Review
- A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis.Blood · 2016Article
- HDAC6 is a Regulator of CTL Function through Control of Lytic Granule Dynamics.Single cell biology · 2016Article
- Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma.The Journal of clinical investigation · 2015Article
- The pool of preactivated Lck in the initiation of T-cell signaling: a critical re-evaluation of the Lck standby model.Immunology and cell biology · 2015Article
- The therapeutic target Hsp90 and cancer hallmarks.Current pharmaceutical design · 2013Review
- Article
- Increased levels of survivin, via association with heat shock protein 90, in mucosal T cells from patients with Crohn's disease.Gastroenterology · 2012Article
- Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus.Cellular & molecular immunology · 2012Article
- Regulated binding of importin-α to protein kinase Cδ in response to apoptotic signals facilitates nuclear import.The Journal of biological chemistry · 2011Article
- Suppressor of cytokine signaling 1 interacts with oncogenic lymphocyte-specific protein tyrosine kinase.Oncology reports · 2011Article
- Tyrosine phosphorylation of tau by the SRC family kinases lck and fyn.Molecular neurodegeneration · 2011Article
- Regulation of activation-induced deaminase stability and antibody gene diversification by Hsp90.The Journal of experimental medicine · 2010Article
- RhoH regulates subcellular localization of ZAP-70 and Lck in T cell receptor signaling.PloS one · 2010Article
- Geldanamycin selectively targets the nascent form of ERBB3 for degradation.Cell stress & chaperones · 2010Article
- Constitutively active Lck kinase in T cells drives antigen receptor signal transduction.Immunity · 2010Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Regulation of the Src-related tyrosine kinase Lck is crucial to the outcome of T-cell receptor (TCR) stimulation. It was previously shown that the stability of the constitutively active mutant LckY505F is controlled by Hsp90 (M. J. Bijlmakers and M. Marsh, Mol. Biol. Cell. 11:1585-1595, 2000). Here we establish that following TCR stimulation, endogenous activated Lck in T cells is also degraded in the presence of the Hsp90 inhibitor geldanamycin. Using Lck constructs expressed in COS-7 cells, we show that the presence of activating Lck mutations results not only in the enhanced dependence on Hsp90 but also in enhanced ubiquitination of Lck. Although both processes were induced by mutations Y505F and W97A that release the SH2 and SH3 inhibitory intramolecular interactions, respectively, neither process required Lck kinase activity or activation-dependent phosphorylation at serines 42 and 59 or tyrosine 394. By binding to the ATP-binding site, the Src family inhibitor PP2 reduced ubiquitination and overcame the need for Hsp90 monitoring of active Lck. We conclude that the levels of active Lck are influenced by two opposing processes, targeting for degradation by ubiquitination and rescue from degradation by Hsp90 monitoring. Based on the PP2 result, we propose that activation-induced conformational changes of the Lck kinase domain instigate both regulatory processes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.