Intracellular CD24 Inhibits Cell Invasion by Posttranscriptional Regulation of BART through Interaction with G3BP

Taniuchi, Keisuke; Nishimori, Isao; Hollingsworth, Michael A.

doi:10.1158/0008-5472.can-10-2743

Cited by 63 publications

(85 citation statements)

References 31 publications

(34 reference statements)

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“…A recent study of pancreatic ductal adenocarcinomas showed that CD24 expression was exclusively up-regulated in well-differentiated tumors, whereas CD24 expression was absent in undifferentiated tumors (33). Our study supports the previous study's proposal that cytoplasmic CD24 expression inhibits tumor cell migration thus inhibiting undifferentiated features (33,34).…”

Section: Discussionsupporting

confidence: 91%

Up-regulation of Cytoplasmic CD24 Expression Is Associated with Malignant Transformation but Favorable Prognosis of Colorectal Adenocarcinoma

Yeo

Lee

Seong

et al. 2016

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Section: Discussionsupporting

confidence: 91%

Up-regulation of Cytoplasmic CD24 Expression Is Associated with Malignant Transformation but Favorable Prognosis of Colorectal Adenocarcinoma

Yeo

Lee

Seong

et al. 2016

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“…1D). We confirmed that knockdown of BART in S2-013 and PANC-1 enhanced cell motility into a wounded area of confluent cultures compared to control cells (10). BART and ARL2 were both recruited to the leading edges during wound healing of control S2-013 cells (upper panels in Fig.…”

Section: Colocalization Of Bart and Arl2 In Pdac Cellssupporting

confidence: 73%

“…2C). We previously reported that suppression of BART enhanced cell invasiveness in Matrigel invasion assays (10). Pretreatment of control S2-013 cells with C3 induced the same level of invasive activity in the Matrigel assay as that induced by knocking down BART (Fig.…”

Section: Colocalization Of Bart and Arl2 In Pdac Cellsmentioning

confidence: 65%

“…We previously reported that regulation of BART posttranscriptional modification via intracellular CD24 binding to G3BP in stress granules contributes to inhibition of invasion and metastasis of pancreatic ductal adenocarcinoma (PDAC) cells (10). In this study, we report the mechanism by which BART regulates RhoA activity through its binding to ARL2 in PDAC cells.…”

Section: Introductionmentioning

confidence: 81%

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BART inhibits pancreatic cancer cell invasion by inhibiting ARL2-mediated RhoA inactivation

Taniuchi

2011

Int J Oncol

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Abstract. We report that BART plays a role in inhibiting cell invasion by regulating the activity of the Rho GTPase protein RhoA in pancreatic cancer cells. BART was originally identified as a binding partner of ARL2, a small G-protein implicated as a regulator of microtubule dynamics and folding. We show that BART interacts with GTP-bound ARL2 and is required for the binding of GTP-bound ARL2 with active forms of RhoA at leading edges in migrating cancer cells. GTP-bound ARL2 inactivates RhoA and BART prevents ARL2 from regulating RhoA activity. Thus, BART binds to and functions as an inhibitor of ARL2 at leading edges of migrating cells, thereby increasing the amount of active RhoA. Treatment with the Rho inhibitor C3 exoenzyme induces cell invasion by pancreatic cancer cells to the same level as that of cells in which BART is stably knocked down by RNA interference. GTP-bound ARL2 acts as a RhoA inhibitor by a mechanism that involves the induction of actin-cytoskeleton rearrangements. We show that BART decreases actin-cytoskeleton rearrangements by inhibiting ARL2 function and by increasing the amount of active RhoA in pancreatic cancer cells. Our results imply that BART increases active RhoA by inhibiting ARL2 function, which in turn inhibits invasiveness of cancer cells. IntroductionBinder of Arl Two (BART) is a soluble 19-kDa protein that was originally purified from bovine brain and identified as a binding partner of small G-protein ADP-ribosylation factorlike 2 (ARL2) (1). ARL proteins lack the biochemical and genetic activities characteristic of the ADP-ribosylation factor (ARF) family, despite the 40-60% identity between ARF and ARL proteins (2). ARL2 has been implicated as a regulator of microtubule dynamics and folding (3), but its function remains largely unknown. Nuclear magnetic resonance analysis recently showed that BART forms a novel fold composed of six α-helices that form three interlocking L shapes (4). GTP-ARL2 assumes a typical small GTPase fold with a unique N-terminal α-helix conformation (5). The regions involved in the binding of ARL2 to its protein partners localize to these loop regions (4). The interactions between ARL2 and BART involve two interfaces: a conserved N-terminal LLXIL motif of ARL2 embedded in a hydrophobic cleft of BART, and the switch regions of ARL2 that interact with helix α3 of BART (5). This novel partner recognition and binding mode is different from that of other small GTPase-effector interactions and provides the molecular basis for the high specificity of ARL2-BART binding (5).BART interaction with ARL2 affects the transcriptional activity and nuclear retention of signal transducer and activator of transcription 3 (STAT3), which is both a cytoplasmic signaling molecule and a nuclear transcription factor (6). Recent studies have linked STAT3 to the metastatic progression of several different cancer types. Studies using mouse embryo fibroblasts established STAT3 as a component of the Rho GTPase-signaling cascade (7,8). Rho GTPases are important regulators of bot...

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“…We previously reported that binder of Arl two (BART) inhibits retroperitoneal invasion and liver metastasis of pancreatic ductal adenocarcinoma (PDAC) cells in an orthotopic xenograft model (12). Our findings provide an explanation for the oncogenic function of G3BP to induce tumor invasion and metastasis by mediating BART mRNA decay.…”

Section: Introductionmentioning

confidence: 53%

The N-Terminal Domain of G3BP Enhances Cell Motility and Invasion by Posttranscriptional Regulation of BART

Taniuchi

Nishimori

Hollingsworth³

2011

Molecular Cancer Research

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The regulation of mRNA stability plays an important role in the control of gene expression during cell motility and invasion. We previously reported that GTPase-activating protein [Src homology 3 (SH3) domain] binding protein (G3BP), a marker of cytoplasmic stress granules that are formed in stressed cells and regulate mRNA stability, binds and degrades the mRNA of binder of Arl two (BART) that inhibits retroperitoneal invasion and hepatic metastasis of pancreatic cancer cells. Here, we report that overexpression of the amino (N)-terminal region of G3BP, including the binding region for BART mRNA, dominant-negatively inhibits formation of the complex between endogenous G3BP and BART mRNA, and increases the expression of BART. This, in turn, inhibits the invasiveness of pancreatic cancer cells. On the other hand, the carboxy (C)-terminal region of G3BP is associated with phosphorylation of eukaryotic translation initiation factor 2a (eIF2a) that initiates stress granule assembly but does not modulate the posttranscriptional regulation of BART mRNA. N-terminal G3BP also plays a role in regulating secreted matrix metalloproteinases, transcription factors, and a variety of genes involved in cell adhesion and motility. These results suggest that N-terminal G3BP contributes to posttranscriptional regulation of cell motility and invasive capacity of pancreatic cancer. Mol Cancer Res; 9(7); 856-66. Ó2011 AACR.

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Intracellular CD24 Inhibits Cell Invasion by Posttranscriptional Regulation of BART through Interaction with G3BP

Cited by 63 publications

References 31 publications

Up-regulation of Cytoplasmic CD24 Expression Is Associated with Malignant Transformation but Favorable Prognosis of Colorectal Adenocarcinoma

Up-regulation of Cytoplasmic CD24 Expression Is Associated with Malignant Transformation but Favorable Prognosis of Colorectal Adenocarcinoma

BART inhibits pancreatic cancer cell invasion by inhibiting ARL2-mediated RhoA inactivation

The N-Terminal Domain of G3BP Enhances Cell Motility and Invasion by Posttranscriptional Regulation of BART

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