Involvement of Ras and Ral in Chemotactic Migration of Skeletal Myoblasts

Suzuki, Jotaro; Yamazaki, Y.; Li, Guang; Kaziro, Yoshito; Koide, Hiroshi

doi:10.1128/mcb.20.18.7049-7049.2000

Cited by 41 publications

(62 citation statements)

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“…Furthermore, essential roles for Ral have been demonstrated in cell migration (Suzuki et al, 2000;Takaya et al, 2004;Oxford et al, 2005;Rosse et al, 2006), and, more locally, in the induction of lamellipodial protrusion at the front of migrating cells (Takaya et al, 2004). We have shown that PI3K, Cdc42, and Rac play important role in such localized activation of Ral (Takaya et al, 2004).…”

Section: Introductionmentioning

confidence: 89%

“…However, Ral may be also activated by calcium signaling pathways (Hofer et al, 1998). In C2C12 myoblasts and some other cell types, growth factors activate Ral in a manner dependent not only on Ras but also on calcium or PI3K signaling pathway (Suzuki et al, 2000;Tian et al, 2002;Takaya et al, 2004). In contrast to GEFs, our knowledge of GAP is extremely limited and to date, proteins exhibiting Ral GAP activity are yet to be identified.…”

mentioning

confidence: 95%

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Akt–PDK1 Complex Mediates Epidermal Growth Factor-induced Membrane Protrusion through Ral Activation

Yoshizaki

Mochizuki

Gotoh

et al. 2007

MBoC

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We studied the spatiotemporal regulation of Akt (also called protein kinase B), phosphatidylinositol-3,4-bisphosphate [PtdIns(3,4)P 2 ], and phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P 3 ] by using probes based on the principle of fluorescence resonance energy transfer. On epidermal growth factor (EGF) stimulation, the amount of PtdIns(3,4,5)P 3 was increased diffusely in the plasma membrane, whereas that of PtdIns(3,4)P 2 was increased more in the nascent lamellipodia than in the plasma membrane of the central region. The distribution and time course of Akt activation were similar to that of increased PtdIns(3,4)P 2 levels, which were most prominent in the nascent lamellipodia. Moreover, we found that upon EGF stimulation 3-phosphoinositide-dependent protein kinase-1 (PDK1) was also recruited to nascent lamellipodia in an Akt-dependent manner. Because PDK1 is known to activate Ral GTPase and because Ral is required for EGF-induced lamellipodial protrusion, we speculated that the PDK1-Akt complex may be indispensable for the induction of lamellipodia. In agreement with this idea, EGF-induced lamellipodia formation was promoted by the overexpression of Akt and inhibited by an Akt inhibitor or a Ral-binding domain of Sec5. These results identified the Akt-PDK1 complex as an upstream positive regulator of Ral GTPase in the induction of lamellipodial protrusion. INTRODUCTIONClass I phosphoinositide 3-kinase (PI3K) is a key mediator of intracellular signaling pathways that regulate actin cytoskeletal reorganization and polarized cell migration. Activated PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P 2 ] to generate phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P 3 ], which, in turn, activates a variety of pleckstrin homology (PH) domain-containing proteins such as Akt (also called protein kinase B) (Saltiel and Pessin, 2002;Sulis and Parsons, 2003). PtdIns(3,4,5)P 3 is dephosphorylated to yield PtdIns(4,5)P 2 by a tumor suppressor protein, phosphatase and tensin homolog deleted in chromosome 10 (PTEN), which is frequently mutated or deleted in various human cancers (Sulis and Parsons, 2003). The resulting PTEN deficiency causes accumulation of PtdIns(3,4,5)P 3 in cells, and, as a consequence, an increase in cell motility in fibroblasts (Liliental et al., 2000;Higuchi et al., 2001;Hafizi et al., 2005). Another dephosphorylated derivative of PtdIns (3,4,5)P 3 is PtdIns(3,4)P 2 produced by phosphoinositide 5-phosphatases, including Src homology 2-containing inositol-5-phosphatase (SHIP). This PtdIns(3,4)P 2 also binds to various PH domain-containing proteins, which overlap significantly to those bound to PtdIns(3,4,5)P 3 (Lemmon and Ferguson, 2000;Maffucci and Falasca, 2001).Among many PH domain-containing proteins, a serinethreonine kinase, Akt, has been studied most extensively. Akt has been implicated in the control of diverse cellular functions, including glucose metabolism, gene transcription, cell proliferation, and apoptosis (Brazil et al., 2004;Fayard et al., 2005)...

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Section: Introductionmentioning

confidence: 89%

mentioning

confidence: 95%

Akt–PDK1 Complex Mediates Epidermal Growth Factor-induced Membrane Protrusion through Ral Activation

Yoshizaki

Mochizuki

Gotoh

et al. 2007

MBoC

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“…These features probably include cell migration and invasiveness -it was shown recently that Ral seems critical for cell motility (Suzuki et al, 2000;Gildea et al, 2002). However, to achieve complete metastatic potential, additional factors might be needed.…”

Section: Discussionmentioning

confidence: 99%

The small G-protein RalA stimulates metastasis of transformed cells

Tchevkina¹,

Agapova²,

Dyakova³

et al. 2004

Oncogene

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RAS oncogenes play a critical role in oncogenic transformation and metastases formation. Here we show that Ha-ras greatly stimulates spontaneous metastatic activity of transformed cells through the Ras/RalGDS/ RalA intracellular signaling pathway. Introduction of RalA alone leads to a drastic increase of metastatic activity of transformed cells. We demonstrate that metastatic ability of cells could be dramatically enhanced by RalA stimulation or, conversely, hampered by RalA suppression. Furthermore, we found that during in vivo selection cells acquire high metastatic properties as a result of endogenous RalA activation. The ability of RalA to induce metastasis was demonstrated in spontaneously transformed as well as in virus transformed fibroblasts.

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“…Endothelial migration is deeply associated with angiogenesis, and migration of skeletal muscle precursor cells is a crucial step in skeletal muscle development and postlesional muscle regeneration. 18,40,41 Therefore, coexpression of both isoforms of HGF, which can be achieved by introducing the alternative splicing function to the expression system, may provide an effective way of inducing neovascularization and regeneration of ischemic tissues in human critical limb ischemia that may result from ischemic diabetic complications and renal failureassociated cases.…”

Section: Coexpression Of Hgf Two Isoforms Improves Critical Limb Ischmentioning

confidence: 99%

“…18,43,40 In all, 24 transwell cell culture chamber inserts (Corning, Corning, NY, USA) with porous polycarbonate filters (8 mm pore size) were coated with 1% gelatin in phosphate-buffered saline. HUVECs or C 2 C 12 suspended in M199 or Dulbecco's modied Eagle's medium supplemented with 1 or 3% of fetal bovine serum, respectively, were added to the inserts at 4 Â 10 4 or 1 Â 10 4 cell per well.…”

Section: Migration Assaymentioning

confidence: 99%

Naked DNA expressing two isoforms of hepatocyte growth factor induces collateral artery augmentation in a rabbit model of limb ischemia

et al. 2010

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Hepatocyte growth factor (HGF) has been shown to induce angiogenesis in vivo and has potential as a candidate gene for 'therapeutic angiogenesis'. In vivo, two isoforms of HGF, HGF 723 and HGF 728 , consisting of 723 and 728 amino acids, are generated through alternative splicing between exons 4 and 5, but the biological effects of their coexpression have not yet been elucidated. In this study, we generated a series of genomic-complementary DNA (cDNA) hybrids of the HGF gene by inserting various truncated intron 4 into the junction of exons 4 and 5 of HGF cDNA and analyzed the biological activities of these hybrid constructs. We showed that: (1) the hybrid called HGF-X7, which contained 1502 base pairs of intron 4, could drive a higher level of HGF expression than other hybrid constructs and cDNAs of each isoform alone; (2) the pCK vector was most efficient for the gene expression of HGF-X7; (3) coexpression of both isoforms of HGF could more efficiently induce the migration of human umbilical vein endothelial cell (HUVEC) and of the mouse myoblast cell line C 2 C 12 myoblasts than a single isoform of HGF and human vascular endothelial growth factor (VEGF) 165 at a given concentration; (4) intramuscular administration of pCK-HGF-X7 resulted in transient and localized HGF expression in the injected muscle without an increase in the HGF protein levels in other tissues including serum; and (5) intramuscular injection of pCK-HGF-X7 could more efficiently increase the number of angiographically recognizable collateral vessels, as well as improve an intra-arterial Doppler wiremeasured blood flow in the rabbit model of hindlimb ischemia when compared with the identical vector encoding VEGF 165 gene. These results showed that transfer of the genomiccDNA hybrid of the HGF gene could be used as a potential therapeutic approach to human vascular diseases.

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Involvement of Ras and Ral in Chemotactic Migration of Skeletal Myoblasts

Cited by 41 publications

References 0 publications

Akt–PDK1 Complex Mediates Epidermal Growth Factor-induced Membrane Protrusion through Ral Activation

Akt–PDK1 Complex Mediates Epidermal Growth Factor-induced Membrane Protrusion through Ral Activation

The small G-protein RalA stimulates metastasis of transformed cells

Naked DNA expressing two isoforms of hepatocyte growth factor induces collateral artery augmentation in a rabbit model of limb ischemia

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