Differential distribution of Rac1 and Rac3 GTPases in the developing mouse brain: implications for a role of Rac3 in Purkinje cell differentiation

Bolis, Annalisa; Corbetta, Sara; Cioce, Antonella; Curtis, Iván de

doi:10.1046/j.1460-9568.2003.02938.x

Cited by 76 publications

(84 citation statements)

References 28 publications

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“…This was somewhat surprising considering the high level of sequence identity shared by these two family members. However, differences in the distribution of Rac1 and Rac3 in the brain have been reported (59), as well as their ability to interact with downstream effectors to promote cell spreading and cell adhesion (60). The alsin-Rac1 interaction may reflect an additional level of functional specificity among the Rac isoforms.…”

Section: Discussionmentioning

confidence: 99%

Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor

Topp

Gray

Gerard

et al. 2004

Journal of Biological Chemistry

173

157

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ALS2 is the gene mutated in a recessive juvenile form of amyotrophic lateral sclerosis (ALS2). ALS2 encodes a large protein termed alsin, which contains a number of predicted cell signaling and protein trafficking sequence motifs. To gain insight into the overall function of alsin and to begin to evaluate its role in motor neuron maintenance, we examined the subcellular localization of alsin and the biochemical activities associated with its individual subdomains. We found that the Vps9p domain of alsin has Rab5 guanine nucleotide exchange activity. In addition, alsin interacted specifically with and acted as a guanine nucleotide exchange factor for Rac1. Immunofluorescence and fractionation experiments in both fibroblasts and neurons revealed that alsin is a cytosolic protein, with a significant portion associated with small, punctate membrane structures. Many of these membrane structures also contained Rab5 or Rac1. Upon overexpression of full-length alsin, the overexpressed material was largely cytosolic, indicating that the association with membrane structures could be saturated. We also found that alsin was present in membrane ruffles and lamellipodia. These data suggest that alsin is involved in membrane transport events, potentially linking endocytic processes and actin cytoskeleton remodeling.Amyotrophic lateral sclerosis (ALS) 1 is a heterogeneous neurological disorder characterized by progressive degeneration of motor neurons, usually causing death as a result of respiratory paralysis (1, 2). Although mostly sporadic in nature, a genetic link has been established in 5-10% of ALS cases (3). Chromosomal mapping studies have identified six independent loci associated with the familial forms of ALS (Refs. 4 -10; reviewed in Refs. 11 and 12). Molecular genetic analysis identified two genes that, when mutated, lead to ALS. The first discovered was the gene coding for Cu-Zn superoxide dismutase 1 (SOD1) (10). Initially, mutations in SOD1 were thought to result in defective free radical scavenger activity. However, it is now generally accepted that the alterations in SOD1 that lead to ALS are the result of an unknown, but toxic gain-of-function. The second gene identified is mutated in a juvenile form of ALS, ALS2 (13,14). Mutations in this gene lead to a rare recessive form of ALS that presents early in life and progresses much more slowly than the classical form (6, 15). Two small deletions in ALS2 were originally associated with the disease (13,14). Each is expected to severely truncate the predicted protein product of ALS2. In addition, mutations in ALS2 have recently been associated with two other neurodegenerative disorders, juvenile-onset primary lateral sclerosis (14) and infantile-onset hereditary spastic paralegia (16 -18). Like the original mutations identified, these mutations are predicted to generate prematurely truncated forms of the protein product.The protein encoded by ALS2, alsin, is predicted to contain numerous domains implicating roles in cell signaling, membrane localization, and protein...

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Section: Discussionmentioning

confidence: 99%

Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor

Topp

Gray

Gerard

et al. 2004

Journal of Biological Chemistry

173

157

View full text Add to dashboard Cite

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“…S1 a). Rac3 has not previously been studied in hemopoietic cells, largely because its expression is highest in neurons (Bolis et al, 2003). However, it has previously been shown to have an opposing effect to Rac1 in neuronal cell adhesion and differentiation (Hajdo-Milasinović et al, 2007).…”

Section: Rhoa Is Required For T Cell Temmentioning

confidence: 99%

Coordinated RhoA signaling at the leading edge and uropod is required for T cell transendothelial migration

Heasman¹,

Carlin²,

Cox³

et al. 2010

J Exp Med

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“…Protein concentrations were determined by the Bradford method and equal amounts of protein were separated by SDS-PAGE. Expression levels of Rac3 were determined by immunoblotting using a Rac3-specific rabbit polyclonal antibody, kindly provided by Dr I de Curtis (Milano, Italy; Bolis et al 2003). Equal protein loading was confirmed by re-incubating the same membranes with a mouse monoclonal antibody against GAPDH (Abcam; dilution 1:5000).…”

Section: Protein Extraction and Rac3 Immunoblottingmentioning

confidence: 99%

“…So far, only two Rac3-specific antibodies have been described in the literature (Haataja et al 1997, Bolis et al 2003. Of these, one antibody was recently found to cross-react with another yet unknown protein of approximately the same molecular weight as Rac3 (Cho et al 2005), strongly limiting its applicability.…”

Section: Evaluating Rac3 Expression In Prostate Cancer and Its Benignmentioning

confidence: 99%

“…Of these, one antibody was recently found to cross-react with another yet unknown protein of approximately the same molecular weight as Rac3 (Cho et al 2005), strongly limiting its applicability. Thus, the only Rac3-specific antibody available so far is the one generated by Dr Ivan de Curtis' group (Bolis et al 2003). However, this antibody is unsuitable for immunohistochemistry on paraffin-embedded tissues (Dr I de Curtis, personal communication).…”

Section: Evaluating Rac3 Expression In Prostate Cancer and Its Benignmentioning

confidence: 99%

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Prognostic relevance of increased Rac GTPase expression in prostate carcinomas

Engers¹,

Ziegler²,

Mueller³

et al. 2007

Endocr Relat Cancer

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Rac proteins of the Rho-like GTPase family, including the ubiquitous Rac1, the hematopoiesisspecific Rac2, and the least-characterized Rac3 play a major role in oncogenic transformation, tumor invasion and metastasis. However, the prognostic relevance of Rac expression in human tumors has not been investigated yet. In the present study, Rac protein expression was analyzed in benign secretory epithelium, high-grade prostatic intraepithelium neoplasia (HG-PIN), and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Thus, Rac proteins were significantly strongly expressed in HG-PIN (P!0.001) and prostate carcinomas (P!0.001) when compared with benign secretory epithelium. Accordingly, all tumor tissues analyzed by isoform-specific real-time PCR (nZ7) exhibited significantly higher RNA expression levels of Rac (i.e. sum of Rac1 and Rac3 expression levels) than the respective benign counterparts (PZ0.018) and this appeared to result mainly from increased expression of the Rac3 isoform as verified by immunoblotting. Univariate analyses showed statistically significant associations of increased Rac protein expression in prostate cancer (PZ0.045), preoperative prostate-specific antigen levels (PZ0.044), pT stage (PZ0.002), and Gleason score (PZ0.001) with decreased disease-free survival (DFS). This prognostic effect of increased protein expression of Rac remained significant even in a multivariate analysis including all these four factors (relative riskZ3.22, 95% confidence intervalZ1.04-10.00; PZ0.043). In conclusion, our data suggest that increased Rac protein expression in prostate cancer relative to the corresponding benign secretory epithelium is an independent predictor of decreased DFS and appears to result mainly from increased expression of the Rac3 isoform.

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Differential distribution of Rac1 and Rac3 GTPases in the developing mouse brain: implications for a role of Rac3 in Purkinje cell differentiation

Cited by 76 publications

References 28 publications

Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor

Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor

Coordinated RhoA signaling at the leading edge and uropod is required for T cell transendothelial migration

Prognostic relevance of increased Rac GTPase expression in prostate carcinomas

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