Oncogenic K-Ras down-regulates Rac1 and RhoA activity and enhances migration and invasion of pancreatic carcinoma cells through activation of p38

Dreissigacker, Ute; Mueller, Meike S.; Unger, Monika; Siegert, Patrizia; Genze, Felicitas; Gierschik, Peter; Giehl, Klaudia

doi:10.1016/j.cellsig.2005.09.004

Cited by 51 publications

(56 citation statements)

References 45 publications

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“…10). The different levels of stimulation of Fer, Fyn, or Src tyrosine kinases by this oncogene might help to explain the divergent results observed for RhoA activity in cells transfected with K-ras (9,31,38).…”

Section: Discussionmentioning

confidence: 99%

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

Castaño

Solanas

Casagolda

et al. 2007

Molecular and Cellular Biology

114

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p120-catenin is an adherens junction-associated protein that controls E-cadherin function and stability. p120-catenin also binds intracellular proteins, such as the small GTPase RhoA. In this paper, we identify the p120-catenin N-terminal regulatory domain as the docking site for RhoA. Moreover, we demonstrate that the binding of RhoA to p120-catenin is tightly controlled by the Src family-dependent phosphorylation of p120-catenin on tyrosine residues. The phosphorylation induced by Src and Fyn tyrosine kinases on p120-catenin induces opposite effects on RhoA binding. Fyn, by phosphorylating a residue located in the regulatory domain of p120-catenin (Tyr112), inhibits the interaction of this protein with RhoA. By contrast, the phosphorylation of Tyr217 and Tyr228 by Src promotes a better affinity of p120-catenin towards RhoA. In agreement with these biochemical data, results obtained in cell lines support the important role of these phosphorylation sites in the regulation of RhoA activity by p120-catenin. Taken together, these observations uncover a new regulatory mechanism acting on p120-catenin that contributes to the fine-tuned regulation of the RhoA pathways during specific signaling events.E-cadherin function is controlled posttranslationally by a family of proteins, named catenins, that bind to its cytosolic tail. Two members of this family, p120-catenin and ␤-catenin, interact at different sites of the E-cadherin molecule and are engaged in distinct functions. Whereas ␤-catenin is required for recruiting the actin cytoskeleton, p120-catenin is necessary for the stabilization of E-cadherin at the cell membrane (3). As a consequence, E-cadherin is rapidly internalized and degraded in the absence of p120-catenin (7, 13). Consequently, p120-catenin ablation in vivo causes E-cadherin deficiency, leading to severe defects in adhesion, cell polarity, and epithelial morphogenesis (7).Besides this role in regulating E-cadherin stability, p120-catenin interacts with other proteins involved in the modulation of cell-to-cell contacts. For instance, p120-catenin associates with Fer and Fyn tyrosine kinases (16,27,36). These kinases specifically phosphorylate ␤-catenin in Tyr142 (27), a modification that promotes release of ␤-catenin from the adherens junctional complex and transport to the nucleus (2, 27). Moreover, p120-catenin can interact with the Yes tyrosine kinase (27) and with a number of phosphotyrosine (PTyr) phosphatases, such as PTP (39), DEP1 (12), and SHP-1 (14, 21). These multiple associations suggest a role for p120-catenin as a scaffold protein for enzymes regulating events such as the stability of the adherens junctional complex (29).p120-catenin modulates the activity of other cellular factors. Similarly to ␤-catenin, it can be detected in the nucleus (34), where it interacts with the transcriptional factor Kaiso (6). Studies performed with Xenopus laevis have demonstrated that association of p120-catenin relieves the repression caused by Kaiso on Wnt signaling (17,25).Several results indicate that p...

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Section: Discussionmentioning

confidence: 99%

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

Castaño

Solanas

Casagolda

et al. 2007

Molecular and Cellular Biology

114

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“…This effect may involve Rac1/PI3K activation and up-regulation of MMP-2/9 (matrix metalloproteinase 2 and 9) (120). Additional studies also showed that p38 phosphorylation is required for K-Ras dependent invasion in pancreatic cancer (121) as well as for prostate (122) and lung cancer invasion (123). Although studies with over-expressed dominant negative p38 proteins showed that only p38alpha (but not other isoforms) is required for H-Ras-induced invasion in 3T3 cells (124), p38gamma proteins were recently shown to promote breast cancer invasion downstream of Ras (73).…”

Section: The Roles Of the P38 Pathway In Regulating Cell Invasion Andmentioning

confidence: 99%

The p38 MAPK stress pathway as a tumor suppressor or more?

Loesch¹

2008

Front Biosci

100

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Abstractp38 mitogen-activated protein kinases (p38 MAPKs) are a group of serine/threonine protein kinases that together with ERK (extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinases) MAPKs act to convert different extracellular signals into specific cellular responses through interacting with and phosphorylating downstream targets. In contrast to the mitogenic ERK pathway, mammalian p38 MAPK family proteins (alpha, beta, gamma, and delta), with and without JNK participation, predominantly regulate inflammatory and stress response. Recent emerging evidence suggests that the p38 stress MAPK pathway may function as a tumor suppressor through regulating Ras-dependent and -independent proliferation, transformation, invasion and cell death by isoform-specific mechanisms. A selective activation of a stress pathway to block tumorigenesis may be a novel strategy to control human malignancies. KeywordsThe p38 MAPK pathway; Ras; Tumor Suppressor; isoform-specific; Oncogenesis; Review INTRODUCTIONMAPKs (mitogen-activated protein kinases) consist of ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase), and p38 cascades (1, 2). Classically, MAPKs function by phosphorylating substrates containing consensus sequence Ser/Thr-Pro (3) after they are phosphorylated and activated by upstream kinases (MAPK kinases). Each of these MAPK pathways has several family members but all share the same conservative Thr-XaaTyr phosphorylation motif (where Xaa is any amino-acid) (1, 2, 4). The ERK activity is mostly frequently activated by mitogens and required for cell proliferation, differentiation and/or transformation (5, 6). JNK and p38 pathways, on the other hand, are predominantly responsive to stress and cytokine signaling and play an in important role in regulating stress response and inflammation (7,8). MAPKs can be activated almost by all type of stimuli and are consequently involved in many critical biological processes such as proliferation, differentiation, cell death and transformation through regulating downstream gene expression and/or interacting with other signaling cascades.Send correspondence to: Dr. Guan Chen, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, gchen@mcw.edu. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe p38 upstream activators include MAPK kinase 6 (MKK6) and MKK3. Downstream effectors consist of kinases such as MK2 (MAPK-activating protein kinase 2) and PRAK (p38-related/activated protein kinase) as well as transcription factors including ATF-2 (activating transcription factor-2), MEF2 (myocyte enhancement factor 2), and c-Jun (4, 9). The mammalian p38 family consists of four isoform proteins (alpha, beta, gamma, and delta), with p38alpha and p38beta 75% identical in their amino-acid sequence, and p38gamma and p38delta about 60% identical to p38alpha (4, 10). p38alpha and p38beta are susceptible to inhibition by SB drugs (SB203580 and SB202190) wh...

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“…5B and C). We (30) and others (36) have shown previously that TGF-ß1 activates the p38 MAPK pathway in Panc-1 cells which is involved in K-ras-mediated cell migration in these cells (37). It was therefore of interest to analyse whether specific Src inhibition affected p38 phosphorylation in these cells.…”

Section: Src Inhibition Does Not Interfere With Tgf-ß1-induced Rsmad mentioning

confidence: 99%

Differential roles of Src in transforming growth factor-ß regulation of growth arrest, epithelial-to-mesenchymal transition and cell migration in pancreatic ductal adenocarcinoma cells

Ungefroren

Sebens²,

Groth³

et al. 2011

Int J Oncol

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Abstract. Both transforming growth factor (TGF)-ß and the non-receptor tyrosine kinase Src play major roles during tumorigenesis by regulating cell growth, epithelial-to-mesenchymal transition (EMT), migration/invasion and metastasis, but little is known about the signaling crosstalk between them. To interfere with Src function in vitro and in vivo many studies have employed the pharmacologic Src inhibitors PP2 and PP1. Both agents have recently been shown to be powerful inhibitors of TGF-ß receptor type I/ALK5 and type II. As this situation prohibited any definite conclusions with respect to the relative contribution of TGF-ß vs. Src signaling, we decided to reappraise a potential role of Src in TGF-ß1-mediated cellular responses using RNA and dominant-negative (dn) interference to block Src expression and function, respectively. In TGF-ß-responsive pancreatic ductal adenocarcinoma (PDAC) cells, we show that Src is activated by TGF-ß1 and that its specific inhibition strongly attenuated basal proliferation and enhanced TGF-ß1-mediated growth arrest. However, Src inhibition was unable to impair TGF-ß1-controlled EMT as evidenced by cell morphology and regulation of the epithelial marker E-cadherin. Despite its dispensibility for TGF-ß-induced EMT, specific inhibition of Src dramatically reduced basal and TGF-ß1-induced cell migration in Panc-1 cells as measured with a novel real-time migration assay (xCELLigence DP system). Biochemically, dnSrc inhibition failed to block TGF-ß1/ALK5-induced activation of Smad2 and Smad3, but partially inhibited transcriptional activation of TGF-ß/Smad-responsive reporter genes, and effectively blocked basal and TGF-ß1-induced activation of p38 MAPK. Together, the data provide evidence for a role of Src in the regulation of basal proliferation as well as in basal and TGF-ß1-mediated cell motility but not EMT in TGF-ß-responsive pancreatic (tumor) cells. IntroductionSrc kinases are non-receptor intracellular tyrosine kinases that mediate a variety of cellular responses. The prototype member p60Src is the product of the proto-oncogene c-Src, and is the cellular homolog of the Rous sarcoma virus transforming protein v-Src. Src kinases are involved in numerous signaling pathways controlling proliferation, migration, adhesion, and angiogenesis (1). Src together with · V ß3 integrin promotes anchorage-independent growth and metastasis (2) and recent data have revealed that transient activation of Src by immortalized mammary epithelial cells triggered an inflammatory response that resulted in the initiation and maintenance of cellular transformation and a switch from a non-transformed to a transformed phenotype (3). Src mediates signaling from many types of receptors including receptor tyrosine kinases (EGF-R), integrins, and G-protein-coupled receptors such as proteinase-activated receptors (PARs) (4). Src is required for EGF-R stimulated DNA synthesis and has been reported to stimulate IGF-I-dependent cell proliferation by increasing IGF-I receptor number (5). Moreover, overexpression...

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Oncogenic K-Ras down-regulates Rac1 and RhoA activity and enhances migration and invasion of pancreatic carcinoma cells through activation of p38

Cited by 51 publications

References 45 publications

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

The p38 MAPK stress pathway as a tumor suppressor or more?

Differential roles of Src in transforming growth factor-ß regulation of growth arrest, epithelial-to-mesenchymal transition and cell migration in pancreatic ductal adenocarcinoma cells

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