Epidermal Growth Factor Activates the Rho GTPase-activating Protein (GAP) Deleted in Liver Cancer 1 via Focal Adhesion Kinase and Protein Phosphatase 2A

Ravi, Archna; Kaushik, Shelly; Ravichandran, Aarthi; Pan, Catherine; Low, Boon Chuan

doi:10.1074/jbc.m114.616839

Cited by 24 publications

(22 citation statements)

References 43 publications

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“…Phosphorylation by CDK5 reduces the binding and places DLC1 in an open confirmation, allowing stronger interaction with tensin and others [24]. In addition to CDK5, Low’s lab has recently shown that DLC1 is phosphorylated by MEK/ERK on T301 and S308 sites and the phosphorylation is critical for activation of its RhoGAP activity [25], which supports our cancer mutation screening results mentioned above. Our current finding has added a new spin on Li’s model in that binding of TNS1 (also TNS2 and TNS3) actually reduces the RhoGAP activity of DLC1, instead of increases as in their report.…”

Section: Discussionsupporting

confidence: 76%

Tensin1 positively regulates RhoA activity through its interaction with DLC1

Shih

Sun

Wang

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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DLC1 is a RhoGAP-containing tumor suppressor and many of DLC1’s functions are absolutely dependent on its RhoGAP activity. Through its RhoGAP domain, DLC1 inhibits the activity of RhoA GTPase, which regulates actin cytoskeleton networks and dis/assembly of focal adhesions. Tensin1 (TNS1) is a focal adhesion molecule that links the actin cytoskeleton to integrins and forms signaling complexes through its multiple binding domains. Here, we report that TNS1 enhances RhoA activity in a DLC1-dependent manner. This is accomplished by binding to DLC1 through TNS1’s C2, SH2, and PTB domains. Point mutations at these three sites disrupt TNS1’s interaction with DLC1 as well as its effect on RhoA activity. The biological relevance of this TNS1-DLC1-RhoA signaling axis is investigated in TNS1 knockout (KO) cells and mice. Endothelial cells isolated from TNS1 KO mice or those silenced with TNS1 siRNA show significant reduction in proliferation, migration, and tube formation activities. Concomitantly, the RhoA activity is down-regulated in TNS1 KO cells and this reduction is restored by further silencing of DLC1. Furthermore, the angiogenic process is compromised in TNS1 KO mice. These studies demonstrate that TNS1 binds to DLC1 and fine-tunes its RhoGAP activity toward RhoA and that the TNS1-DLC1-RhoA signaling axis is critical in regulating cellular functions that lead to angiogenesis.

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Section: Discussionsupporting

confidence: 76%

Tensin1 positively regulates RhoA activity through its interaction with DLC1

Shih

Sun

Wang

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…GAPs promote the transition from GTP to GDP [20, 21]. Although several GAPs have been indicated as major regulators in multiple cancers [22, 23], the mechanisms underlying GAPs are understudied. ARHGAP24 (also known as FilGAP) is expressed ubiquitously in majority of tissues, with the highest expression level in kidney [17], suggesting an essential role in renal cell development.…”

Section: Discussionmentioning

confidence: 99%

ARHGAP24 inhibits cell cycle progression, induces apoptosis and suppresses invasion in renal cell carcinoma

Huang

et al. 2016

Oncotarget

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Renal cell carcinoma (RCC) is the major cause of kidney malignancy-related deaths. Rho GTPases are key regulators in cancer cell metastasis. ARHGAP24, a Rac-specific member of the Rho GTPase-activating protein family, acts as a functional target of cancer cell migration and invasion. In the present study, we identified ARHGAP24 expression is downregulated in renal cancer tissues and is highly correlated with long-term survival in RCC patients. Therefore, we investigated the biological functions of ARHGAP24 in renal cancer cells. Ectopic expression of ARHGAP24 resulted in inhibited cell proliferation and arrested cell cycle in two renal cancer cell lines (786-0 and Caki-2); the results were confirmed by ARHGAP24 knocking down. In addition, ARHGAP24 significantly reduced the cell invasion ability and induced apoptosis in renal cancer cells. In addition, overexpressing ARHGAP24 impaired tumor formation in vivo. In summary, our results illustrated that ARHGAP24 plays a unique role in RCC progression as a tumor repressor.

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“…; Ravi et al. ), and packaged using commercial envelope and packaging plasmid preparations (Addgene, Cambridge, MA). High‐efficiency plasmid delivery was obtained using TransIT‐LT1 (Mirus‐Bio, Madison, WI) in serum‐free MEM (OptiMEM, Sigma) with 3 μ L of TransIT‐LT1 per μ g of DNA, incubated with the plasmids for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Chloride-hydrogen antiporters ClC-3 and ClC-5 drive osteoblast mineralization and regulate fine-structure bone patterning in vitro

et al. 2015

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Osteoblasts form an epithelium-like layer with tight junctions separating bone matrix from extracellular fluid. During mineral deposition, calcium and phosphate precipitation in hydroxyapatite liberates 0.8 mole of H+ per mole Ca+2. Thus, acid export is needed for mineral formation. We examined ion transport supporting osteoblast vectorial mineral deposition. Previously we established that Na/H exchangers 1 and 6 are highly expressed at secretory osteoblast basolateral surfaces and neutralize massive acid loads. The Na/H exchanger regulatory factor-1 (NHERF1), a pdz-organizing protein, occurs at mineralizing osteoblast basolateral surfaces. We hypothesized that high-capacity proton transport from matrix into osteoblast cytosol must exist to support acid transcytosis for mineral deposition. Gene screening in mineralizing osteoblasts showed dramatic expression of chloride–proton antiporters ClC-3 and ClC-5. Antibody localization showed that ClC-3 and ClC-5 occur at the apical secretory surface facing the bone matrix and in membranes of buried osteocytes. Surprisingly, the Clcn3−/− mouse has only mildly disordered mineralization. However, Clcn3−/− osteoblasts have large compensatory increases in ClC-5 expression. Clcn3−/− osteoblasts mineralize in vitro in a striking and novel trabecular pattern; wild-type osteoblasts form bone nodules. In mesenchymal stem cells from Clcn3−/− mice, lentiviral ClC-5 shRNA created Clcn3−/−, ClC-5 knockdown cells, validated by western blot and PCR. Osteoblasts from these cells produced no mineral under conditions where wild-type or Clcn3−/− cells mineralize well. We conclude that regulated acid export, mediated by chloride–proton exchange, is essential to drive normal bone mineralization, and that CLC transporters also regulate fine patterning of bone.

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Epidermal Growth Factor Activates the Rho GTPase-activating Protein (GAP) Deleted in Liver Cancer 1 via Focal Adhesion Kinase and Protein Phosphatase 2A

Cited by 24 publications

References 43 publications

Tensin1 positively regulates RhoA activity through its interaction with DLC1

Tensin1 positively regulates RhoA activity through its interaction with DLC1

ARHGAP24 inhibits cell cycle progression, induces apoptosis and suppresses invasion in renal cell carcinoma

Chloride-hydrogen antiporters ClC-3 and ClC-5 drive osteoblast mineralization and regulate fine-structure bone patterning in vitro

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