ARHGAP8 is a novel member of the RHOGAP family related to ARHGAP1/CDC42GAP/p50RHOGAP: mutation and expression analyses in colorectal and breast cancers

Johnstone, Cameron N.; Castellví–Bel, Sergi; Chang, Laura M.; Bessa, Xavier; Nakagawa, Hiroshi; Harada, Hideki; Sung, Raphael K.; Piqué, Josep M.; Castells, Antoni; Rustgi, Anil K.

doi:10.1016/j.gene.2004.01.025

Cited by 51 publications

(38 citation statements)

References 28 publications

(38 reference statements)

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“…For oligonucleotide sequences of the PCR primer pairs used, see the supplemental materials and methods. Normal human colon was obtained from the Cooperative Human Tissue Network at the hospital of the University of Pennsylvania, and total RNA was isolated from the purified epithelium as described previously (27).…”

Section: Methodsmentioning

confidence: 99%

“…Student's t test for means was applied for evaluation of expression level differences using SPSS (version 12) statistical software (SPSS Inc., Chicago, IL). Frozen primary human breast tumors were obtained from the Cooperative Human Tissue Network at the hospital of the University of Pennsylvania, and cDNA was synthesized as previously described (27).…”

Section: Methodsmentioning

confidence: 99%

“…31 within an approximately 1-Mb region that undergoes frequent loss of heterozygosity in sporadic breast cancers (7,27) and mismatch repair-proficient colorectal cancers (6,27). Mutational analysis of PARVG in sporadic breast and colorectal tumors revealed several germ line polymorphisms but no evidence of somatic mutations (8).…”

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confidence: 99%

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Parvin-β Inhibits Breast Cancer Tumorigenicity and Promotes CDK9-Mediated Peroxisome Proliferator-Activated Receptor Gamma 1 Phosphorylation

Johnstone

Mongroo

Rich

et al. 2008

Molecular and Cellular Biology

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The integrin-linked kinase (ILK) is a multifunctional adaptor protein and serine/threonine kinase that binds the cytoplasmic domains of ␤1-and ␤3-integrin receptor subunits (18,19,68). ILK is a key constituent of the molecular bridge between cell surface integrins and the cortical actin cytoskeleton, namely, focal adhesion complexes (32,49,57). In addition to a structural role, integrin-extracellular matrix (ECM) engagement or stimulation with growth factors activates ILK kinase activity in a phosphatidylinositol 3Ј kinase-dependent manner, resulting in phosphorylation of downstream substrates, such as AKT Ser473 and glycogen synthase kinase 3␤ Ser9 (13). ILK also provides integrins with a connection to certain receptor tyrosine kinases via the adaptor proteins PINCH1/2 and NCK2 (64, 72). Overexpression of ILK in cell lines results in anchorage-independent growth, E-cadherin loss, increased invasiveness, and tumorigenicity in nude mice (13,19). Moreover, increased ILK expression and activity in mouse mammary tumor virus ILK transgenic mice leads to mammary hyperplasias and breast cancers (67). These data suggest that ILK activity must be regulated carefully for effective tumor suppression in vivo and raise the possibility that modulators of ILK function or kinase activity could be deregulated during epithelial oncogenesis.Parvin-␣, -␤, and -␥ comprise a small family of widely expressed ILK-binding proteins with tandem calponin homology domains (30,48,51,57,70). The two best-characterized members, Parvin-␣ and -␤, interact directly with the ILK kinase domain in a mutually exclusive manner (73) and modulate both its kinase activity and connections to the actin cytoskeleton (51), although the molecular mechanisms underlying these actions are only now beginning to emerge (43,66,73). Less is known about Parvin-␥ function.Data from several studies suggest that Parvin-␣ and Parvin-␤ may have divergent actions in the regulation of ILK signaling and cytoskeletal dynamics. For example, Parvin-␣ was reported to facilitate ILK-mediated phosphorylation of AKT Ser473, with subsequent protection from apoptosis (13, 73), whereas Parvin-␤ overexpression in HeLa cells promoted apoptosis (73). Parvin-␤ also inhibited ILK kinase activity and reduced AKT Ser473 and glucogen synthase kinase 3␤ Ser9 phosphorylation in response to epidermal growth factor stimulation, as previously reported by us (43), consistent with negative regulation of ILK signaling. In contrast to Parvin-␣, Parvin-␤ directly bound to the actin-binding protein ␣-actinin and was required for proper focal adhesion formation, lamellipodium maturation, and cell spreading (69, 70). In addition to its reg-* Corresponding author. Mailing address:

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Parvin-β Inhibits Breast Cancer Tumorigenicity and Promotes CDK9-Mediated Peroxisome Proliferator-Activated Receptor Gamma 1 Phosphorylation

Johnstone

Mongroo

Rich

et al. 2008

Molecular and Cellular Biology

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“…This domain, spanning approximately 100−200 residues, is composed of seven α-helices and is sufficient for productive interaction with Rho targets [18,24]. RhoGAP are usually large proteins possessing several additional functional domains implicated in regulation, membrane targeting and localization [16,25]. Here, most of RhoGAP members examined have other domains besides RhoGAP domain.…”

Section: Discussionmentioning

confidence: 99%

New member of the guanosine triphosphatase activating protein family in the human epididymis

Xiangqi¹,

Li²,

Qiang³

et al. 2008

ABBS

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The effect of the guanosine triphosphatase activating proteins (GAPs) on spermatogenesis has been studied for years, though no GAPs have been explored in epididymis, an essential organ for sperm maturation. In this study, a new GAP member, designated as MacGAP, was cloned in human epididymis. The MacGAP gene encodes a protein of 618 amino acids with a putative size of 70 kDa and harbors the conserved RhoGAP domain. The N-terminal and C-terminal peptides of MacGAP were expressed and their corresponding antisera were prepared. The antisera against N-terminal peptide could detect antigen as low as 0.3 ng, and its specificity was also confirmed. However, the antisera against C-terminal peptide failed to detect its antigen because of its low sensitivity. Immunohistochemistry showed that the MacGAP protein was dependent on epididymis and had a region-specific expression pattern, with high expression in the epithelial cells' basal section in the caput region. The results have created a foundation for further interpretation of the biological effects of GAPs in sperm maturation.

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“…Deletion or downregulation of these GAPs leads to increased levels of GTP-bound RhoA and thus enhanced GTPase activity and downstream signalling, which could contribute to tumourigenesis. ARHGAP8 is a Rho GAP which has been found to be upregulated in the majority of colon tumours [124].…”

Section: Gapsmentioning

confidence: 99%

Rho GTPases: functions and association with cancer

Ellenbroek

Collard

2007

Clin Exp Metastasis

246

210

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Rho GTPases are small proteins that act as binary molecular switches in a wide range of signalling pathways upon stimulation of cell surface receptors. Three different classes of regulatory proteins control their activity. In the activated state small GTPases are able to bind a variety of effector proteins and initiate downstream signalling. Rho GTPases regulate important cellular processes ranging from cytoskeletal remodelling and gene expression to cell proliferation and membrane trafficking. Therefore it is not surprising that deregulated Rho signalling can contribute to disturbed cellular phenotypes in a wide range of diseases. The main focus of this review will be the diversity of functions of Rho GTPases and the effects of aberrant Rho GTPase signalling in various aspects of cancer.

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ARHGAP8 is a novel member of the RHOGAP family related to ARHGAP1/CDC42GAP/p50RHOGAP: mutation and expression analyses in colorectal and breast cancers

Cited by 51 publications

References 28 publications

Parvin-β Inhibits Breast Cancer Tumorigenicity and Promotes CDK9-Mediated Peroxisome Proliferator-Activated Receptor Gamma 1 Phosphorylation

Parvin-β Inhibits Breast Cancer Tumorigenicity and Promotes CDK9-Mediated Peroxisome Proliferator-Activated Receptor Gamma 1 Phosphorylation

New member of the guanosine triphosphatase activating protein family in the human epididymis

Rho GTPases: functions and association with cancer

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