rho-mediated protein tyrosine phosphorylation in lysophosphatidic-acid-induced tumor-cell invasion

Imamura, Fumio; Shinkai, Kiyoko; Mukai, Mutsuko; Yoshioka, Kiyoko; Rika, Komagome; Iwasaki, Teruo; Akedo, Hitoshi

doi:10.1002/(sici)1097-0215(19960301)65:5<627::aid-ijc12>3.0.co;2-4

Cited by 66 publications

(44 citation statements)

References 17 publications

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“…Although the rho genes have been suspected to be involved in cell transformation, there are few reports about rho gene expressions in human tumour tissues. Recently, in vitro assay revealed that activated RhoA protein is necessary for the motility of keratinocytes induced by hepatocyte growth factor (Takaishi et al, 1994) and that the invasive activity of rat MM 1 cells across the mesothelial cell monolayer is inhibited by Clostridium boturinum exo-enzyme C3 that specifically inactivates Rho proteins (Imamura et al, 1996). Serum-dependent invasional activity of hepatoma cells is regulated by activated RhoA protein (Yoshioka et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas

Suwa

Ohshio²,

Imamura³

et al. 1998

Br J Cancer

246

242

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Summary It has been reported that the rho genes, which consist of a ras-related small GTPase protein family, regulate cytoskeletal structures and have the potential to transform cultured cells. To investigate the biological relevance of the rho genes in pancreatic carcinogenesis, we examined expressions of the rhoA, B and C genes by polymerase chain reaction after reverse transcription (RT-PCR) in 33 cases of ductal adenocarcinoma of the pancreas. In addition, mutations of the K-ras, rhoA, B and C genes were studied in the same series of tumour tissues to correlate with rho gene expressions. The expression levels of the rhoC gene were significantly higher in tumours than in non-malignant portions (P < 0.001). Metastatic lesions overexpressed the rhoC gene compared with primary tumours (P < 0.05). Carcinoma tissues with perineural invasion and lymph node metastasis exhibited significantly higher expressions of the rhoC gene than tumours without these manifestations (P < 0.001 and P < 0.05 respectively). Overexpression of the rhoC gene significantly correlated with poorer prognosis of patients with pancreatic adenocarcinoma (P < 0.05). In contrast, the expression levels of the rhoA and B genes showed no significant relationship with clinicopathological findings. Mutation was not found either in the rhoA, B or C gene sequences examined. K-ras gene mutation, detected in 27 out of 33 (81.8%) cases, did not affect the expression levels in any of the rho genes. These suggest that elevated expression of the rhoC gene may be involved in the progression of pancreatic carcinoma independent of K-ras gene activation.

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Section: Discussionmentioning

confidence: 99%

Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas

Suwa

Ohshio²,

Imamura³

et al. 1998

Br J Cancer

246

242

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“…Signal transduction cascades mediated by Rho GTPases originate via the extracellular stimulation of transmembrane receptors such as G protein-coupled receptors (GPCRs), 4 receptor tyrosine kinases, cytokine receptors, and integrins. Of the 22 human Rho family members, RhoA, Rac1, and Cdc42 are the most characterized, stemming from their ability to induce striking changes in cellular morphology upon activation (3).…”

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confidence: 99%

Gαq Directly Activates p63RhoGEF and Trio via a Conserved Extension of the Dbl Homology-associated Pleckstrin Homology Domain

Rojas

Yohe

Gershburg

et al. 2007

Journal of Biological Chemistry

143

169

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The coordinated cross-talk from heterotrimeric G proteins to Rho GTPases is essential during a variety of physiological processes. Emerging data suggest that members of the G␣ 12/13 and G␣ q/11 families of heterotrimeric G proteins signal downstream to RhoA via distinct pathways. Although studies have elucidated mechanisms governing G␣ 12/13 -mediated RhoA activation, proteins that functionally couple G␣ q/11 to RhoA activation have remained elusive. Recently, the Dbl-family guanine nucleotide exchange factor (GEF) p63RhoGEF/GEFT has been described as a novel mediator of G␣ q/11 signaling to RhoA based on its ability to synergize with G␣ q/11 resulting in enhanced RhoA signaling in cells. We have used biochemical/biophysical approaches with purified protein components to better understand the mechanism by which activated G␣ q directly engages and stimulates p63RhoGEF. Basally, p63RhoGEF is autoinhibited by the Dbl homology (DH)-associated pleckstrin homology (PH) domain; activated G␣ q relieves this autoinhibition by interacting with a highly conserved C-terminal extension of the PH domain. This unique extension is conserved in the related Dbl-family members Trio and Kalirin and we show that the C-terminal Rhospecific DH-PH cassette of Trio is similarly activated by G␣ q .Rho GTPases are integral regulators of gene transcription and actin cytoskeletal remodeling during many dynamic cellular processes (1, 2). Signal transduction cascades mediated by Rho GTPases originate via the extracellular stimulation of transmembrane receptors such as G protein-coupled receptors (GPCRs), 4 receptor tyrosine kinases, cytokine receptors, and integrins. Of the 22 human Rho family members, RhoA, Rac1, and Cdc42 are the most characterized, stemming from their ability to induce striking changes in cellular morphology upon activation (3). Numerous studies have established that RhoA activation downstream of GPCRs is vital for a multitude of diverse physiological responses including cell migration (4), lipid metabolism (5), vascular smooth muscle cell contraction (6 -8), and cell survival/apoptosis (9 -12). GPCR-mediated activation of RhoA effectively couples signaling pathways mediated by two distinct groups of guanine nucleotide-binding proteins: the heterotrimeric G␣-subunits and the monomeric small GTPases. These two groups of G proteins share a universal mechanism for guanine nucleotide binding, GTP hydrolysis, and conformational switching between two discrete states: a GDPbound inactive state and a GTP-bound active state (13). Guanine nucleotide exchange factors (GEFs) activate G proteins by promoting the release of bound GDP, allowing the subsequent binding of GTP. Active, GTP-bound G proteins can then interact with numerous downstream effector molecules, further propagating the signal initiated at the plasma membrane.GPCRs function as GEFs for heterotrimeric G␣-subunits, whereas Dbl-family GEFs are the major class of exchange factors for Rho GTPases. Dbl-family GEFs are defined by the presence of a Dbl homology domain (DH doma...

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“…These events have been demonstrated to occur downstream of RhoA and to be closely involved in transcellular migration. 20,21,24 Moreover, because anti-fibronectin (FN) antibodies (Abs), anti-␤1 integrin Abs and cyclo-GRGDSPA remarkably suppressed LPAinduced migration, the interaction between FN and ␤1 integrin is also necessary for LPA-induced migration of MM1 cells. 25 These findings show that both LPA-induced activation of the RhoA-ROCK pathway and integrin signaling via the FN-␤1 integrin interaction are essential and that paxillin may play an important role in integrating both signals into the migration of MM1 cells.…”

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confidence: 99%

Involvement of phosphorylation of tyr‐31 and tyr‐118 of paxillin in MM1 cancer cell migration

Iwasaki

Nakata

Mukai

et al. 2001

Intl Journal of Cancer

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We demonstrated previously that rat ascites hepatoma MM1 cells require both lysophosphatidic acid (LPA) and fibronectin (FN) for phagokinetic motility and transcellular migration and that these events are regulated through the RhoA-ROCK pathway. It remains to be elucidated, however, how the signals from both LPA and FN are integrated into cell migration. To examine this, total cellular lysates after stimulation with LPA or FN were subjected to time-course immunoblot analysis with anti-phosphotyrosine antibodies (Abs). Consequently, tyrosine-phosphorylation of paxillin was obviously persistent after stimulation with FN ؉ LPA as compared to after stimulation with either alone. Cell migration plays an essential role in various physiological and pathological phenomena such as embryogenesis, wound repair, inflammation and invasion and metastasis of cancer cells. 1,2 Cell migration is primarily mediated by integrin binding to extracellular matrices (ECM) and regulated by organization of the actin cytoskeleton and the formation of focal adhesion complexes, which are induced through activation of the Rho-family small GTP-binding proteins. [3][4][5] Integrins not only act as a scaffold but also generate important signals leading to cell migration. Integrinmediated signaling events that regulate cytoskeletal organization require Rho-family GTPases and conversely integrin-mediated adhesion itself regulates Rho-family GTPases. 6 Cell motility is closely related to morphology, growth, 7 differentiation and survival, in which different signals from other cell surface receptors are also implicated. 8 It remains to be elucidated, however, how the integrin and growth-factor signaling pathways are integrated into cell migration.Paxillin (p68-kD) is one of the integrin assembly proteins and can interact directly with several integrin assembly proteins, including vinculin, talin, ␤1 integrin, focal adhesion kinase (FAK), c-Src and Csk. 9,10 Three human isoforms of paxillin (␣, ␤ and ␥) and 2 homologous murine isoforms (␣ and ␤) have been identified, 11,12 and the ␣ form (original paxillin) appears to play a more dominant role. 13 Integrin-mediated tyrosine phosphorylation also enables paxillin to interact with various signaling molecules: tyrosine residues (Y) 31 and 118 being especially predominant targets of phosphorylation by kinases and creating binding sites for the SH2 domain of adaptor protein Crk. 14 -16 Thus, paxillin plays a pivotal role in cell adhesion, migration and further oncogenic transformation. 9,10 Because several cytokines and growth factors also induce tyrosine phosphorylation of paxillin, 9,10 it is suggested that the signals from both cytokine-and growth-factor receptors and those from integrins converge on paxillin.In efforts to evaluate the invasive capacity of cancer cells and to understand the mechanisms of cancer-host interactions including transcellular (transmonolayer) migration of cancer cells, we have developed an in vitro system: rat ascites hepatoma MM1 cells are allowed to invade a mesothelial cel...

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rho-mediated protein tyrosine phosphorylation in lysophosphatidic-acid-induced tumor-cell invasion

Cited by 66 publications

References 17 publications

Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas

Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas

Gαq Directly Activates p63RhoGEF and Trio via a Conserved Extension of the Dbl Homology-associated Pleckstrin Homology Domain

Involvement of phosphorylation of tyr‐31 and tyr‐118 of paxillin in MM1 cancer cell migration

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