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388 records · Page 22Linked to original sources
PubMed2002

The small GTPase Rho3 and the diaphanous/formin For3 function in polarized cell growth in fission yeast.

We identified a novel Rho gene rho3(+) and studied its interaction with diaphanous/formin for3(+) in the fission yeast Schizosaccharomyces pombe. Both rho3 null cells and for3 null cells showed defects in organization of not only actin cytoskeleton but also cytoplasmic microtubules (MTs). rho3 for3 double null cells had defects that were more severe than each single null cell: polarized growth was deficient in the double null cells. Function of For3 needed the highly conserved FH1 and FH2 domains, an N-terminal region containing a Rho-binding domain, and the C-terminal region. For3 bound to active forms of both Rho3 and Cdc42 but not to that of Rho1. For3 was localized as dots to the ends of interphase cells and to the mid-region in dividing cells. This localization was probably dependent on its interaction with Rho proteins. Overexpression of For3 produced huge swollen cells containing depolarized F-actin patches and thick cytoplasmic MT bundles. In addition, overexpression of a constitutively active Rho3Q71L induced a strong defect in cytokinesis. In conclusion, we propose that the Rho3-For3 signaling system functions in the polarized cell growth of fission yeast by controlling both actin cytoskeleton and MTs.

Cell Cycle Proteins↗
PubMed2005

A novel Rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts.

Osteoclast maturation is accompanied by changes in podosome patterning, resulting in the formation of a peripheral belt, which requires an intact microtubule network. Here, we report that by inhibiting Rho, the podosome belt is maintained at the cell periphery despite depolymerisation of microtubules by nocodazole. Rho inhibition was correlated to the increase in microtubule stabilisation and microtubule acetylation. By microinjecting activated Rho or its activated effector mDia2 in osteoclasts, we found that the podosome belt was disrupted and the level of microtubule acetylation dramatically decreased. We further characterised the molecular mechanism responsible for microtubule deacetylation by co-immunoprecipitation experiments. We found that not only was mDia2 coprecipitating with the recently identified microtubule deacetylase HDAC6 but that it also activated the microtubule deacetylase activity of HDAC6 in an in vitro deacetylase assay. Finally, we found that during osteoclastogenesis, there is a correlation between the increase in microtubule acetylation and the podosome belt stabilisation and that if Rho is inhibited in the early stages of osteoclast differentiation, it accelerates both microtubule acetylation and podosome belt stabilisation. Altogether, our data reveal a pathway in which Rho interferes with the osteoclast maturation process by controlling the level of microtubule acetylation and actin organisation through mDIA2 and HDAC6.

Acetylation↗
PubMed2004

A new look at Rho GTPases in cell cycle: role in kinetochore-microtubule attachment.

Rho GTPases including Rho, Rac and Cdc42 are involved in cell morphogenesis by inducing specific types of actin cytoskeleton and alignment and stabilization of microtubules. Previous studies suggest that they also regulate cell cycle progression; Rho, Rac and Cdc42 regulate the G(1)-S progression and Rho controls cytokinesis. However, a role of Rho GTPases in nuclear division has not been definitely shown. We have recently found that Cdc42 and its downstream effector mDia3 are involved in bi-orientation and stabilization of spindle microtubules attachment to kinetochores and regulate chromosome alignment and segregation. Here, we discuss how this is coordinated with other events in mitosis, particularly, with the action of Rho in cytokinesis and how attachment of microtubules to kinetochores is achieved and stabilized. We also discuss redundancy of dc42 and Cdc42-related GTPase(s) and potential mechanisms of chromosome instability in cancer.

Animals↗
PubMed2004

[Diagnosis of genetically determined hearing impairment--difficulties and problems].

In terms of growing interest in molecular analysis of genetically determined hearing impairment, it is of clinical importance to know problems and obstacles that arise on the way to molecular diagnosis. Although for clinicians a genetic factor as a reason for hearing problem is easier accepted, still an understanding the limits of such identification remains unclear. Technical issues, as well as social and legal aspects of genetic analysis are described. Authors try to explain why such impressive progress in understanding of hearing loss physiology, especially from the genetic point of view, does not have its transfer into clinical practice.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Regulation of microtubules by Rho GTPases in migrating cells.

Microtubules (MTs) contribute to cell polarization and migration, but the molecular mechanism involved are unknown. We have explored signalling pathways that generate specific changes in MTs arrays in wounded monolayers of fibroblasts. In earlier work, we found that Rho GTPase and its effector mDia, stimulate selective MT stabilization in the lamella, whereas Cdc42 and the MT motor protein dynein regulate MT organizing centre (MTOC) reorientation towards the leading edge. We have now found that the MT tip proteins EB1 and adenomatous polyposis coli protein (APC) function with mDia to stabilize MTs and interact directly with mDia. EB1, APC and mDia localize to the ends of stabilized MTs suggesting that they may contribute to capping of these MTs. Models of MTOC reorientation suggest that the MTOC moves in front of the nucleus by dynein pulling on MTs. In contrast, we find by directly imaging MTOC reorientation that the nucleus moves rearward while the MTOC remains stationary. Rearward nuclear movement is coupled to retrograde actin-myosin flow and is regulated by Cdc42 and its effector myotonic dystrophy kinase-related Cdc42-binding kinase. Dynein is not involved in nuclear movement, but is essential to maintain the MTOC at the cell centroid. These results show that there are two Cdc42 pathways that regulate MTOC reorientation.

Animals↗
PubMed2006

[Actin dynamics].

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Actin Cytoskeleton↗
PubMed2006

Function of rax2p in the polarized growth of fission yeast.

Cell polarity is critical for the division, differentiation, migration, and signaling of eukaryotic cells. RAX2 of budding yeast encodes a membrane protein localized at the cell cortex that helps maintain the polarity of the bipolar pattern. Here, we designate SPAC6f6.06c as rax2+ of Schizosaccharomyces pombe, based on its sequence homology with RAX2, and examine its function in cell polarity. S. pombe rax2+ is not essential, but Deltarax2 cells are slightly smaller and grow slower than wild type cells. During vegetative growth or arrest at G1 by mutation of cdc10, deletion of rax2+ increases the number of cells failing old end growth just after division. In addition, this failure of old end growth is dramatically increased in Deltatea1Deltarax2, pointing to genetic interaction of rax2+ with tea1+. Deltarax2 cells contain normal actin and microtubule cytoskeletons, but lack actin cables, and the polarity factor for3p is not properly localized at the growing tip. In Deltarax2 cells, and endogenous rax2p is localized at the cell cortex of growing cell tips in an actin- and microtubule-dependent manner. However, Deltarax2 cells show no defects in cell polarity during shmoo formation and conjugation. Taken together, these observations suggest that rax2p controls the cell polarity of fission yeast during vegetative growth by regulating for3p localization.

Actins↗
PubMed1997

Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous.

The gene responsible for autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive hearing loss in a large Costa Rican kindred was previously localized to chromosome 5q31 and named DFNA1. Deafness in the family is associated with a protein-truncating mutation in a human homolog of the Drosophila gene diaphanous. The truncation is caused by a single nucleotide substitution in a splice donor, leading to a four-base pair insertion in messenger RNA and a frameshift. The diaphanous protein is a profilin ligand and target of Rho that regulates polymerization of actin, the major component of the cytoskeleton of hair cells of the inner ear.

Actins↗