Identification of proteins binding the native tubulin dimer

Gache, Vincent; Louwagie, Mathilde; Garin, Jérôme; Caudron, Nicolas; Lafanéchère, Laurence; Valiron, Odile

doi:10.1016/j.bbrc.2004.11.138

Cited by 25 publications

(20 citation statements)

References 46 publications

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“…This analysis allowed us to identify HSP70/GRP75 among the protein associated to TUBB3. This finding supports that GRP78/GRP75 and HSP/HSC70 play the cooperative role of molecular chaperones in formation and function of the eukaryotic cell cytoskeleton (31). Interestingly, we also found that FMO4 forms a complex mediated by disulfide bridges with TUBB3.…”

Section: Discussionsupporting

confidence: 87%

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Cicchillitti¹,

Penci²,

Michele

et al. 2008

Molecular Cancer Therapeutics

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Class III B-tubulin (TUBB3) has been discovered as a marker of drug resistance in human cancer. To get insights into the mechanisms by which this protein is involved in drug resistance, we analyzed TUBB3 in a panel of drug-sensitive and drug-resistant cell lines. We identified two main different isoforms of TUBB3 having a specific electrophoretic profile. We showed that the apparently higher molecular weight isoform is glycosylated and phosphorylated and it is localized in the cytoskeleton. The apparently lower molecular weight isoform is instead found exclusively in mitochondria. We observed that levels of phosphorylation and glycosylation of TUBB3 are associated with the resistant phenotype and compartmentalization into cytoskeleton. By two-dimensional nonreduced/reduced SDS-PAGE analysis, we also found that TUBB3 protein in vivo forms protein complexes through intermolecular disulfide bridges. Through TUBB3 immunoprecipitation, we isolated protein species able to interact with TUBB3. Following trypsin digestion, these proteins were characterized by mass spectrometry analysis. Functional analysis revealed that these proteins are involved in adaptation to oxidative stress and glucose deprivation, thereby suggesting that TUBB3 is a survival factor able to directly contribute to drug resistance. Moreover, glycosylation of TUBB3 could represent an attractive pathway whose inhibition could hamper cytoskeletal compartmentalization and TUBB3 function.

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Section: Discussionsupporting

confidence: 87%

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Cicchillitti¹,

Penci²,

Michele

et al. 2008

Molecular Cancer Therapeutics

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“…All three proteins have been implicated in cancer progression [32][33][34] and all three bind to cytoskeleton proteins and influence cytoskeleton dynamics and organisation. [35][36][37] In particular, changes in B23 expression alters the balance between stress fibre formation and other more dynamic forms of F actin. 37 Interestingly, Hsp60 and members of the Hsp70 family are also substrates for TG2.…”

Section: Discussionmentioning

confidence: 99%

The role of Lamin A in cytoskeleton organization in colorectal cancer cells

Foster¹,

Robson²,

Simon³

et al. 2011

Nucleus

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“…In particular, the constitutively expressed isoform of Hsp70, Hsc70/ Hsp73/HSPA8, accounts for 2% of total protein in cells and affects a number of processes including cytoskeletal function and clathrin-mediated endocytosis (14). Hsc70 associates with both intact MTs (15)(16)(17)(18)(19) and tubulin directly through its nucleotidebinding domain (NBD), suggesting functional regulation of tubulin by Hsc70 beyond proteostasis (20). Hsc70 also interacts with the microtubule (MT)-associated protein (MAP) tau, a putative 'typical' client of Hsc70 (6,(21)(22)(23) further suggesting that Hsc70 uniquely regulates MT dynamics (24,25).…”

Section: Introductionmentioning

confidence: 99%

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

Fontaine¹,

Martin²,

Akoury³

et al. 2015

Human Molecular Genetics

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The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)-associated protein that functions to maintain MT stability, is implicated in a number of hereditary and sporadic neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease. Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target. In particular, the constitutive Hsp70 isoform, Hsc70, seems highly interconnected with tau, preserving tau protein levels and synergizing with it to assemble MTs. But the relationship between tau and Hsc70, as well as the impact of this interaction in neurons and its therapeutic implications remain unknown. Using a human dominant negative Hsc70 that resembles isoform selective inhibition of this important chaperone, we found for the first time that Hsc70 activity is required to stimulate MT assembly in cells and brain. However, surprisingly, active Hsc70 also requires active tau to regulate MT assembly in vivo, suggesting that tau acts in some ways as a co-chaperone for Hsc70 to coordinate MT assembly. This was despite tau binding to Hsc70 as substrate, as determined biochemically. Moreover, we show that while chronic Hsc70 inhibition damaged MT dynamics, intermittent treatment with a small molecule Hsp70 inhibitor lowered tau in brain tissue without disrupting MT integrity. Thus, in tauopathies, where MT injury would be detrimental to neurons, the unique relationship of tau with the Hsc70 machinery can be exploited to deplete tau levels without damaging MT networks.

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Identification of proteins binding the native tubulin dimer

Cited by 25 publications

References 46 publications

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

The role of Lamin A in cytoskeleton organization in colorectal cancer cells

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

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