Specific accumulation of Rho-associated kinase at the cleavage furrow during cytokinesis: cleavage furrow-specific phosphorylation of intermediate filaments

Kosako, Hidetaka; Goto, Hidemasa; Yanagida, Maki; Matsuzawa, Kaori; Fujita, Masatoshi; Tomono, Yasuko; Okigaki, Tohru; Odai, Hideharu; Kaibuchi, Kozo; Inagaki, Masaki

doi:10.1038/sj.onc.1202633

Cited by 112 publications

(105 citation statements)

References 38 publications

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“…Future studies evaluating the extent and duration of WFA retention in tumor tissue will fully characterize the disposition and pharmacodynamic properties of WFA in preventing metastatic growth. Vimentin phosphorylation regulates vimentin dynamics [42][43][44][45] and ser56 phosphorylation is associated with cell motility signaling pathways. 40,46 Specifically, vimentin ser56 phosphorylation inversely regulates PAK activation and is critical for vimentin filament spatial rearrangement elicited by agonists.…”

Section: Cancer Therapymentioning

confidence: 99%

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Thaiparambil

Bender

Ganesh

et al. 2011

Intl Journal of Cancer

223

208

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Withaferin A (WFA) is purified from the plant Withania somnifera and inhibits the vimentin cytoskeleton. Vimentin overexpression in cancer correlates with metastatic disease, induction of epithelial to mesenchymal transition and reduced patient survival. As vimentin functions in cell motility, we wanted to test the hypothesis that WFA inhibits cancer metastasis by disrupting vimentin function. These data showed that WFA had weak cytotoxic and apoptotic activity at concentrations less than or equal to 500 nM, but retained potent anti-invasive activity at these low doses. Imaging of breast cancer cell lines revealed that WFA induces perinuclear vimentin accumulation followed by rapid vimentin depolymerization. A concomitant induction of vimentin ser56 phosphorylation was observed, which is consistent with vimentin disassembly. Structure activity relationships were established using a set of chemically modified WFA analogs and showed that the predicted vimentin-binding region of WFA is necessary to induce vimentin ser56 phosphorylation and for its anti-invasive activity. Pharmacokinetic studies in mice revealed that WFA reaches peak concentrations up to 2 lM in plasma with a half-life of 1.36 hr following a single 4 mg/kg dose. In a breast cancer metastasis mouse model, WFA showed dose-dependent inhibition of metastatic lung nodules and induced vimentin ser56 phosphorylation, with minimal toxicity to lung tissue. Based upon these studies, we conclude that WFA is a potent breast cancer anti-metastatic agent and the anti-metastatic activity of WFA is, at least in part, mediated through its effects on vimentin and vimentin ser56 phosphorylation.Metastatic disease is the major cause of death in almost all cancer types; however, most treatments are developed to target the primary tumor and not the metastases. This is due to metastatic cells being difficult to detect, highly aggressive, chemoresistant and experimentally challenging to model. 1 At present, there is no agent in clinical use that effectively prevents metastasis and most patients ultimately succumb to metastatic disease.The metastatic process can be broadly categorized into three stages-tumor cell invasion into surrounding tissue, intravasation into blood or lymphatic vessels and extravasation into a new host environment. These events are triggered by genetic and epigenetic alterations that transform stationary epithelial cells into migratory cells, a process termed epithelialmesenchymal transition (EMT). 2,3 Recent data suggests that cancer cells can re-trigger EMT to migrate into surrounding tissue. 3,4 A classical EMT protein is vimentin; numerous reports show that vimentin is overexpressed in invasive human tumors but is nearly undetectable in non-invasive, stationary tumors. 3,[5][6][7] Vimentin is a Type III intermediate filament 8 and its overexpression correlates with metastatic disease, EMT induction, poor prognosis and reduced patient survival. 7,[9][10][11] Similar correlations between vimentin overexpression and invasion are observed in cancer ce...

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Section: Cancer Therapymentioning

confidence: 99%

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Thaiparambil

Bender

Ganesh

et al. 2011

Intl Journal of Cancer

223

208

View full text Add to dashboard Cite

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“…ROCK1 and ROCK2 are essentially cytosolic in the resting state, but are translocated to membrane upon Rho activation [74,82]. In addition, ROCK2 has been found to be located at cleavage furrows during cytokinesis [65], at stress fiber [14] and vimentin intermediate filament network [128], whereas ROCK1 has been shown to be co-localized with the centrosomes [15]. Two recent reports, using siRNA approach, have shown that ROCK1 and ROCK2 have distinct distributions in primary rat embryonic fibroblasts [151] and are involved with different myosin compartments [151,152].…”

Section: Structure and Expression Of Rock Isoformsmentioning

confidence: 99%

Rho kinase in the regulation of cell death and survival

Shi

Wei

2007

Arch. Immunol. Ther. Exp.

211

183

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SummaryRho kinase (ROCK) belongs to a family of serine/threonine kinases that are activated via interaction with Rho GTPases. ROCK is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, and proliferation. Recent studies have shown that ROCK plays an important role in the regulation of apoptosis in various cell types and animal disease models. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be function redundant, based largely on kinase construct overexpression, and chemical inhibitors (Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiological and patho-physiological functions of the two ROCK isoforms. This review, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in the regulation of apoptosis and highlights the new findings from recently generated ROCK-deficient mice.

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“…These six amino acid residues are highly conserved among species, implying the biological importance of GFAP phosphorylation [7]. Enzymes including protein kinase A (PKA), protein kinase C (PKC), calcium/calmodulin dependent protein kinase II (CaMKII), Rho kinase, cleavage furrow (CF) kinase and Cdc2 kinase modulate the phosphorylation of one or more of the GFAP residues [8][9][10][11][12]. Phosphorylation in the N-terminal region (head domain) affects GFAP assembly and in the C-terminal region (tail domain), phosphorylation of Ser-389 affects interactions between GFAP and other intermediate filaments or proteins [10].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of GFAP is Associated with Injury in the Neonatal Pig Hypoxic-Ischemic Brain

Sullivan

Miller

et al. 2012

Neurochem Res

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Glial fibrillary acidic protein (GFAP) is an intermediate filament protein expressed in the astrocytecytoskeleton that plays an important role in the structure and function of the cell. GFAP can be phosphorylated at six serine (Ser) or threonine (Thr) residues but little is known about the role of GFAP phosphorylation in physiological and pathophysiological states. We have generated antibodies against two phosphorylated GFAP (pGFAP) proteins: p8GFAP, where GFAP is phosphorylated at Ser-8 and p13GFAP, where GFAP is phosphorylated at Ser-13. We examined p8GFAP and p13GFAP expression in the control neonatal pig brain and at 24h and 72h after an hypoxic-ischemic (HI) insult. Immunohistochemistry demonstrated pGFAP expression in astrocytes with an atypical cytoskeletal morphology, even in control brains. Semi-quantitative western blotting revealed that p8GFAP expression was significantly increased at 24h post-insult in HI animals with seizures in frontal, parietal, temporal and occipital cortices. At 72h post-insult, p8GFAP and p13GFAP expression were significantly increased in HI animals with seizures in brain regions that are vulnerable to cellular damage (cortex and basal ganglia), but no changes were observed in brain regions that are relatively spared following an HI insult (brain stem and cerebellum). Increased pGFAP expression was associated with poor neurological outcomes such as abnormal encephalography (EEG) and neurobehaviour, and increased histological brain damage.Phosphorylation of GFAP may play an important role in astrocyte remodelling during development and disease and could potentially contribute to the plasticity of the central nervous system. 3

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Specific accumulation of Rho-associated kinase at the cleavage furrow during cytokinesis: cleavage furrow-specific phosphorylation of intermediate filaments

Cited by 112 publications

References 38 publications

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Rho kinase in the regulation of cell death and survival

Phosphorylation of GFAP is Associated with Injury in the Neonatal Pig Hypoxic-Ischemic Brain

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