Role of the Pi3k Regulatory Subunit in the Control of Actin Organization and Cell Migration

Jiménez, Concepción; Portela, Rosario Armas; Mellado, Mario; Rodrı́guez-Frade, José Miguel; Collard, John G.; Serrano, Antonio; Martı́nez-A, Carlos; Ávila, Jesús; Carrera, Ana C.

doi:10.1083/jcb.151.2.249

Cited by 221 publications

(224 citation statements)

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“…Thus, currently the general picture is that Cdc42 activates Rac, which activates Rho (Matozaki et al, 2000). Evidence of mutual inhibition between Cdc42/Rac and Rho has also been found (Van Leeuwen et al, 1997;Sander et al, 1999;Firtel and Chung, 2000;Jiménez et al, 2000;Zondag et al, 2000;Caron, 2003).…”

Section: Spatial Localization and Crosstalk Of Rho Gtpasesmentioning

confidence: 73%

Polarization and Movement of Keratocytes: A Multiscale Modelling Approach

et al. 2006

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Section: Spatial Localization and Crosstalk Of Rho Gtpasesmentioning

confidence: 73%

Polarization and Movement of Keratocytes: A Multiscale Modelling Approach

et al. 2006

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“…Activation of PI3k, which catalyzes the formation of phosphatidylinositol 3,4,5-phosphate, can influence cell morphology through its effects on actin cytoskeleton reorganization and migration (Jimenez et al, 2000). For Figure 4 Decreased PI3k/Akt phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…If motility depends on Cdc42, then this decrease in Cdc42 may be responsible for the decreased cell motility characterized by the decrease in ruffling. Activation of a pathway involving Cdc42 has been shown to contribute to actin polymerization and cell migration induced by PDGF (Jimenez et al, 2000;Sturge et al, 2002). Since induction of the Cdc42 pathway is independent of PI3k activity but requires the p85alpha regulatory subunit of PI3K, Figure 7 Staurosporine-induced apoptosis in the antisense-uPA clones.…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

Chandrasekar

Mohanam

Gujrati³

et al. 2003

Oncogene

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The ability of glioma cells to migrate great distances from a primary tumor mass is the primary cause of tumor recurrence. The urokinase-type plasminogen activator (uPA) is a serine protease that can initiate proteolytic cascades, which result in remodeling of extracellular matrix and basement membrane, allowing cells to move across and through these barriers. The binding between uPA and its receptor uPAR also mediates several signaling events that seem to contribute to the evolution of a migratory phenotype. In this study, we determined how the downregulation of uPA affects the signaling pathways leading to cell migration. Stably transfecting human glioblastoma cells with antisense uPA decreased the amount of cell-bound uPA and disrupted actin cytoskeleton formation and cell migration. The phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathway has been suggested to mediate migration in various cancer cells. The antisense-uPA clones also had less phosphorylated PI3k and Akt than control cells, a finding associated with decreased cell migration, G2/M-phase arrest, and decreased clonogenic survival. Decreased activation of PI3k and the antiapoptotic factor Akt was not sufficient to induce apoptosis in the antisense-uPA clones, but staurosporine sensitized them to apoptosis to a greater extent than control cells. These results indicate that PI3k/ Akt pathway is involved in the signaling cascade required to induce cell migration and that uPA has a direct role in regulating migration.

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“…Other Rho family members Rac and Cdc42 have also been shown to be transiently activated by PDGF stimulation that lead to the down-regulation of RhoA activity thus attenuating the stress fiber formation (Sander et al, 1999;Jimenez et al, 2000). On the basis of these observations together with our present data, we propose that the PKC-dependent down-regulation of myosin motor activity and the down-regulation of RhoA concertedly control the change in actin cytoskeletal structure upon PDGF stimulation ( Figure 7B).…”

Section: Discussionmentioning

confidence: 99%

The Phosphorylation of Myosin II at the Ser1 and Ser2 Is Critical for Normal Platelet-derived Growth Factor–induced Reorganization of Myosin Filaments

Komatsu

Ikebe

2007

MBoC

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Phosphorylation of the regulatory light chain of myosin II (MLC 20 ) at the activation sites promotes both the motor activity and the filament formation of myosin II, thus playing an important role in various cell motile processes. In contrast, the physiological function of phosphorylation of MLC 20 at the inhibitory sites is unknown. Here we report for the first time the function of the inhibitory site phosphorylation in the cells. We successfully produced the antibodies specifically recognizing the phosphorylation sites of MLC 20 at Ser1, and the platelet-derived growth factor (PDGF)-induced change in the phosphorylation at the Ser1 was monitored. The phosphorylation of MLC 20 at the Ser1 significantly increased during the PDGF-induced actin cytoskeletal reorganization. PDGF disassembled the stress fibers, and this was attenuated with the expression of unphosphorylatable MLC 20 at the Ser1/Ser2 phosphorylation sites. The present results suggest that the down-regulation of myosin II activity achieved by the phosphorylation at the Ser1/Ser2 sites plays an important role in the normal reorganization of actomyosin filaments triggered by PDGF receptor stimulation. INTRODUCTIONCell migration plays a key role in both the physiological and the pathophysiological function of the cells including development, wound healing, immunity, and metastasis (Lauffenburger and Horwitz, 1996). Reorganization of actomyosin filaments is an essential process for these cell behaviors. It has been thought that myosin II plays a fundamental role in various types of cellular motility.In vitro biochemical studies have revealed that the function of smooth muscle and nonmuscle myosin II is regulated by the phosphorylation of MLC 20 (Sellers, 1991;Tan et al., 1992). A number of studies have shown that the phosphorylation of MLC 20 at Thr18 and Ser19 activates its motor activity and increases filament stability. On the other hand, it has been known that MLC 20 can be phosphorylated at other sites different from the activation sites. Originally, it was found that protein kinase C (PKC) phosphorylates Ser1/Ser2 and Thr9 of MLC 20 . This phosphorylation decreases the affinity of myosin II phosphorylated at the activation sites for actin and the affinity of MLC 20 for myosin light-chain kinase (MLCK; Nishikawa et al., 1984;Bengur et al., 1987;Ikebe et al., 1987;Ikebe and Reardon, 1990). In other words, the phosphorylation of MLC 20 at these sites inhibits rather than activates myosin II.It was reported that the phosphorylation of MLC 20 at the Thr9 inhibits myosin II motor activity and the phosphorylation of MLC 20 by MLCK (Nishikawa et al., 1984;Turbedsky et al., 1997); however, phosphorylation of the inhibitory sites in nonmuscle cells has only been observed on Ser1 and/or Ser2, but not on Thr9 in vivo (Kawamoto et al., 1989;Yamakita et al., 1994), and this is because the Ser1/Ser2 sites are resistant to dephosphorylation by myosin light chain phosphatases while phospho-Thr9 is readily dephosphorylated (Ikebe et al., 1999). Furthermore, it has b...

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Role of the Pi3k Regulatory Subunit in the Control of Actin Organization and Cell Migration

Cited by 221 publications

References 50 publications

Polarization and Movement of Keratocytes: A Multiscale Modelling Approach

Polarization and Movement of Keratocytes: A Multiscale Modelling Approach

Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

The Phosphorylation of Myosin II at the Ser1 and Ser2 Is Critical for Normal Platelet-derived Growth Factor–induced Reorganization of Myosin Filaments

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