DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers

Wang, Dunrui; Qian, Xiaolan; Rajaram, Megha; Durkin, Marian E.; Lowy, Douglas R.

doi:10.18632/oncotarget.9266

Cited by 44 publications

(51 citation statements)

References 40 publications

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“…A RhoA pull‐down assay demonstrated a remarkable reduction in RhoA activity in transiently DLC2‐transfected cells . Furthermore, the formation of actin stress fibers in DLC2‐GAP expressing cells was significantly inhibited compared with in non‐transfected cells . In our current study, the knockdown of FKBP51 significantly decreased RhoA activation (Fig.…”

Section: Discussionsupporting

confidence: 62%

“…We identified deleted in liver cancer 1 (DLC1, also known as ARHGAP7 and STARD12) and deleted in liver cancer 2 (DLC2/ARHGAP37/STARD13), which are structurally similar and share the same functional domains (sterile α motif (SAM), Rho‐GAP, and START domains) . Both proteins are underexpressed in certain cancers, and they suppresses tumor cell growth by inhibiting RhoA activity via the Rho‐GAP domain . Their Rho‐GAP activity strongly hydrolyzes Rho‐GTP, weakly hydrolyzes Cdc42‐GTP, and has no detectable activity against Rac‐GTP .…”

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confidence: 99%

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FKBP51 regulates cell motility and invasion via RhoA signaling

et al. 2017

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FK506 binding protein 51 (FKBP51), a member of the immunophilin family, is involved in multiple signaling pathways, tumorigenesis, and chemoresistance. FKBP51 expression correlates with metastatic potential in melanoma and prostate cancer. However, the functions of FKBP51, particularly involving the regulation of cell motility and invasion, are not fully understood. We discovered two novel interacting partner proteins of FKBP51, i.e., deleted in liver cancer 1 (DLC1) and deleted in liver cancer 2 (DLC2), using immunoprecipitation and mass spectrometry. DLC1 and DLC2 are Rho GTPase‐activating proteins that are frequently downregulated in various cancers. Next, we demonstrated that overexpression of FKBP51 enhances cell motility and invasion of U2OS cells via upregulation of RhoA activity and enhanced Rho‐ROCK signaling. Moreover, FKBP51‐depleted cells displayed a cortical distribution of actin filaments and decreased cell motility and invasion. Consistent with this phenotype, FKBP51 depletion caused a downregulation of RhoA activity. Considered together, our results demonstrate that FKBP51 positively controls cell motility by promoting RhoA and ROCK activation; thus, we have revealed a novel role for FKBP51 in cytoskeletal rearrangement and cell migration and invasion.

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Section: Discussionsupporting

confidence: 62%

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confidence: 99%

FKBP51 regulates cell motility and invasion via RhoA signaling

et al. 2017

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“…Clinically, compared with normal or adjacent noncancerous tissues, the DLC1 expression is significantly lower in lung adenocarcinoma and squamous cell carcinoma, breast cancer, HCC, ovarian carcinoma tissues and metastatic melanoma, but not colorectal cancer (Song et al, ). The DLC1 expression is significantly lower in the late stages than in the early stages of cancer and is more downregulated in metastatic than nonmetastatic cancers, which is confirmed by the meta‐analysis (1,815 cancer patients) and the TCGA database (Wang, Qian, Rajaram, Durkin, & Lowy, ). The expression of DLC1, as well as invasion and metastasis of ovarian cancer, is also closely related (Ren, Shi, Zhang, & Zhang, ).…”

Section: Effects Of Natural Products and Drugs On Dlc1mentioning

confidence: 53%

“…The expression of DLC1, as well as invasion and metastasis of ovarian cancer, is also closely related (Ren, Shi, Zhang, & Zhang, ). DLC1 loss as well as poor overall and disease‐specific 5‐year survival rate are significantly correlated (Wang et al, ). DLC1 methylation can also be used for the diagnosis of cancer and further identify those patients with a poor prognosis (Chang et al, ).…”

Section: Effects Of Natural Products and Drugs On Dlc1mentioning

confidence: 99%

A tumor suppressor DLC1: The functions and signal pathways

Zhang

2019

Journal Cellular Physiology

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Deleted in liver cancer‐1 (DLC1), a potential tumor suppressor, acts as a GTPase‐activating protein for Rho family members. In many human cancers, the DLC1 expression is frequently downregulated or inactivated, which allows cancer cells to proliferate and disseminate. In this review, we describe the characteristics and other members of the DLC1 family and delineate the signal pathways DLC1 involved in regulating cancer cell growth, colony formation, apoptosis, senescence, autophagy, migration and invasion. In addition, we explore the clinical data of DLC1 and the mechanisms that natural products upregulate the DLC1 expression to inhibit cancer. Despite these insights, many important unanswered questions remain about the exact mechanisms of DLC1‐mediated cancer suppression.

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“…In cancer, downregulation of DLC1 is also more important than DLC2 and DLC3 [7]. Fibroblasts cultured from DLC1-deficient mouse embryos have shown significant alterations in the cytoskeleton organization of actin filaments and focal adhesions, suggesting a crucial role for DLC1 in these processes in normal cells [2].…”

Section: Dlc1: a Tumor Suppressor That Regulates Rho Signaling Brajenmentioning

confidence: 99%

Untitled

2017

Oncotarget

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Rho GTPases are key transducers of several fundamental cellular processes such as cell division, adhesion, migration, polarity, cytoskeletal remodeling, and apoptosis [3]. They act as molecular switches that cycle between an inactive GDP-bound and an active GTP-bound form in response to intra-or extracellular signaling. This GDP/GTP cycle is carefully controlled by three classes of regulatory proteins: the Rho-GEFs (guanine nucleotide exchange factors) that catalyze the exchange of GDP for GTP, the Rho-GAPs (GTPase activating proteins) that hydrolyze GTP to GDP, and the Rho-GDIs (guanine nucleotide dissociation inhibitors) that form a complex with the GDP-bound form of Rho proteins and prevent nucleotide exchange as well as sequester the Rho GTPases in the cytoplasm. During cell spreading and migration, Rho GTPases control the formation of focal complexes, their maturation to focal adhesions, and the continuous turnover of these structures, along with many aspects of actin cytoskeletal dynamics, including stress fiber formation. Dysregulation of Rho GTPases is associated with diverse abnormal phenotypes and several diseases, including cancer. One Rho regulator that has frequently been implicated in cancer is the tumor suppressor Deleted in Liver Cancer 1 (DLC1; also known as STARD12 or ARHGAP7). DLC1 encodes a Rho-GAP that negatively regulates Rho by converting active GTP-bound Rho to inactive GDP-bound Rho, is associated with focal adhesions, and is down-regulated in many tumor types.The most abundant translation product of the human DLC1 gene, which is located at chromosome 8p21-22, is a 1091 amino acid protein that contains three well recognized domains: an N-terminal sterile alpha motif (SAM) domain, a C-terminal steroidogenic acute regulatory protein-related lipid transfer (START) domain, and the Rho-GAP domain, located upstream from the START domain [1,2,5]. A Serine-rich Linker region (LR) lies between the SAM and the Rho-GAP domains. A segment within the LR is sometimes referred to as the Focal Adhesion Targeting (FAT) domain because DLC1 is recruited to focal adhesions via this region. The multidomain structure of DLC1 suggests that it might interact with several other functionally important proteins, and several DLC1 binding partners, in addition to Rho-GTP, have been identified and found to contribute to the biology of DLC1 [1,5]. Two other structurally related proteins of the DLC family, DLC2 (STARD13), and DLC3 (KIAA0189 or STARD8) have also been identified.Although all three members of the family are widely expressed in normal tissues, only DLC1 knockout mice are embryonic lethal, while DLC2 and DLC3 knockout mice are viable, which suggests DLC1 is essential for embryonic development. In cancer, downregulation of DLC1 is also more important than DLC2 and DLC3 [7]. Fibroblasts cultured from DLC1-deficient mouse embryos have shown significant alterations in the cytoskeleton organization of actin filaments and focal adhesions, suggesting a crucial role for DLC1 in these processes in normal cells [2].D...

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DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers

Cited by 44 publications

References 40 publications

FKBP51 regulates cell motility and invasion via RhoA signaling

FKBP51 regulates cell motility and invasion via RhoA signaling

A tumor suppressor DLC1: The functions and signal pathways

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