RalA requirement for v-Src- and v-Ras-induced tumorigenicity and overproduction of urokinase-type plasminogen activator: involvement of metalloproteases

Aguirre‐Ghiso, Julio A.; Frankel, Paul; Farías, Eduardo; Lu, Zhimin; Jiang, Hong; Olsen, Anne S.; Feig, Larry A.; Joffé, Elisa Bal de Kier; Foster, David A.

doi:10.1038/sj.onc.1202850

Cited by 70 publications

(53 citation statements)

References 38 publications

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“…So far, cellular functions of Ral are still largely enigmatic (45). Evidence has been presented that Ral is activated by Ras via Ral-guanine nucleotide exchange factors by a signal pathway parallel to the Raf/mitogen-activated protein kinase cascade and may be involved in transformation to act downstream of Ras (18,19,46). RalA is suggested to be involved in regulation of the actin cytoskeleton.…”

Section: Resultsmentioning

confidence: 99%

Interaction of the Rho-ADP-ribosylating C3 Exoenzyme with RalA

Wilde¹,

Barth²,

Sehr³

et al. 2002

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Interaction of the Rho-ADP-ribosylating C3 Exoenzyme with RalA

Wilde¹,

Barth²,

Sehr³

et al. 2002

Journal of Biological Chemistry

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“…Furthermore, a FAK-p130 CAS -Crk-Dock180-JNK-MMP-2 pathway was implicated in v-Src-mediated invasion (Hauck et al, 2002b;Hsia et al, 2003). Several other studies have provided evidence for the increased production of MMPs in v-Src-transformed cells (Kadono et al, 1998;Aguirre-Ghiso et al, 1999;Cha et al, 2000;Kurata et al, 2000).…”

Section: Integrins and Cadherinsmentioning

confidence: 97%

The interplay between Src and integrins in normal and tumor biology

2004

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Src family nonreceptor protein tyrosine kinases transduce signals that control normal cellular processes such as cell proliferation, adhesion and motility. Normally, cellular Src is held in an inactive state, but in several cancer types, abnormal events lead to elevated kinase activity of the protein and cause pleiotropic cellular responses inducing transformation and metastasis. A prerequisite of the ability of a cancer cell to undergo metastasis into distant tissues is to penetrate surrounding extracellular matrices. These processes are facilitated by the integrin family of cell adhesion molecules. As is the case with Src, altered integrin activity or substrate affinity can contribute to the neoplastic phenotype. Therefore, understanding the interplay between Src and integrin function has been of intense interest over the past few years. This review focuses on the role of Src and integrin signaling in normal cells and how this is deregulated in human cancer. We will identify the key players in the integrin-mediated signaling pathways involved in cell motility and apoptosis, such as FAK, paxillin and p130 CAS , and discuss how Src signaling affects the formation of focal adhesions and the extracellular matrix.

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“…32 A sustained and increased level of PLD can be deleterious and can contribute to the development of cancer. 37 Because of its important role in progression of cancer, PLD could be a target for cancer therapy. Although the duration and amplitude of PLD signals are important determinants in control of diverse biological processes, including cell proliferation and survival, the mechanisms that regulate quantitative output of PLD signaling remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells

Kang

Park

Kim

et al. 2010

Intl Journal of Cancer

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Phospholipase D (PLD) is an important signaling enzyme implicated in the control of many biological processes, including cell proliferation and survival. Despite the importance of the duration and amplitude of PLD signaling in carcinogenesis, mechanisms that regulate PLD expression remain poorly understood. In our study, we define the regulatory components of the machinery that specifies selective PLD1 induction via signals propagated through PLD activity. We demonstrate for the first time that establishment of a positive feedback loop that is dependent on enzymatic activity originating from both PLD1 and PLD2 isozymes enhances selective expression of PLD1, but not PLD2. Phosphatidic acid, the product of PLD activity, leads to an increase in the Ras-ERK/PI3K-NFjB signaling cascade and enhances binding of NFjB to the PLD1 promoter, consequently inducing selective PLD1 expression in SK-BR3 breast cancer cells. Moreover, selective PLD inhibitor suppressed epidermal growth factor-induced matrix metalloproteinase upregulation and invasion by inhibiting PLD1 expression. In conclusion, we propose that autoregulation of PLD activity might be coupled to induction of PLD1 expression, and thereby play a role in carcinogenesis.Phosphatidic acid (PA) has emerged as an important mediator of lipid signaling that is associated with regulation of cell growth and proliferation, membrane trafficking and cytoskeletal reorganization. Because of its regulatory role, the level of PA itself should be tightly regulated through synthesis and turnover. PA is the product of phosphatidylcholine hydrolysis catalyzed by phospholipase D (PLD) and is strategically located at the intersection of several major signaling and metabolic pathways. Endogenous levels of PA are low in resting cells, and PLD activity is tightly regulated by mechanisms that control secretion, migration, survival and proliferation of cells. 1,2 PLD is activated by a variety of mitogens, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and interleukin 1b (IL-1b), [3][4][5][6][7] and its involvement in many cellular biological processes, including cell proliferation, survival, vesicular trafficking and secretion, has been demonstrated. 1,8 Two distinct isoforms of mammalian PLD, PLD1 and PLD2, have been identified. 9 PLD mediates the parallel reactions of phospholipid hydrolysis and transphosphatidylation. Primary alcohols, such as ethanol or 1-butanol, serve as competitive nucleophiles to water, resulting in a transphosphatidylation reaction that produces a phosphatidylalcohol, such as phosphatidylbutanol (PtdBut), instead of PA. Thus, primary alcohols have been used almost exclusively as the only means of preventing PA production for study of the role of PLD-mediated PA formation in certain cellular processes. 10 Potent dual PLD1 and PLD2 inhibitors, as well as isoformselective PLD inhibitors, with considerable pharmacological characterization have recently been developed. 11 Recent work has demonstrated a novel PA target in the Ras/Raf/ERK si...

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RalA requirement for v-Src- and v-Ras-induced tumorigenicity and overproduction of urokinase-type plasminogen activator: involvement of metalloproteases

Cited by 70 publications

References 38 publications

Interaction of the Rho-ADP-ribosylating C3 Exoenzyme with RalA

Interaction of the Rho-ADP-ribosylating C3 Exoenzyme with RalA

The interplay between Src and integrins in normal and tumor biology

Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells

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