RAC Regulation of Actin Polymerization and Proliferation by a Pathway Distinct from Jun Kinase

Joneson, Tom; McDonough, Michele; Bar–Sagi, Dafna; Aelst, Linda Van

doi:10.1126/science.274.5291.1374

Cited by 250 publications

(246 citation statements)

References 26 publications

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“…As noted previously, double mutants of Rac and CDC42 that are both activated and defective in selective e ector function (analogous to the 75L/49A and 75L/54C double mutants of TC10 studies here) have been instrumental in identifying multiple independent e ector pathways for each of these GTPases (Joneson et al, 1996;Lamarche et al, 1996;Westwick et al, 1997). As shown in Figure 6, introduction of the 49A e ector mutation (analogous to Rac and CDC42 position 35 e ector mutants) into activated TC10 reduces the percentage of transfected cells containing multiple long ®lopodia from 45% to zero, while introduction of the 54C e ector mutation (analogous to Rac and CDC42 40C) reduces this percentage by only about one half.…”

Section: Tc10 Is a Member Of The Rho Family Of Ras-related Gtpasesmentioning

confidence: 69%

“…Non-transfected cells generally show few or no actin-containing cell surface structures (not shown). See Figure 6 for quantitation of data from multiple transfections GTPase defective TC10 stimulates JNK, SRF and NF-kB activation Activated CDC42 and Rac mutants have been shown to stimulate JNK, SRF and NF-kB activation in transient transfection assays (Joneson et al, 1996;Lamarche et al, 1996;Perona et al, 1997;Westwick et al, 1997, for review see Machesky and. These stimulations are presumed to require an intact e ector domain, since mutation at either position 35 or 40 abolishes CDC42-or Rac-mediated activation of JNK and SRF.…”

Section: Tc10 Is a Member Of The Rho Family Of Ras-related Gtpasesmentioning

confidence: 99%

“…Speci®cally, JNK is activated in cells expressing constitutively active CDC42 or Rac. JNK activation, in turn, results in the phosphorylation and activation of the transcription factors c-Jun and Elk-1, which stimulate transcription from genes containing AP-1 and SRE elements, respectively (Joneson et al, 1996;Lamarche et al, 1996;Westwick et al, 1997; for review see Wasylyk et al, 1998). Further supporting a role for CDC42 and Rac in JNK signaling, JNK and cJun are activated in cells over-expressing GEFs that act on Rac and CDC42 (Westwick et al, 1998;Whitehead et al, 1998;Zhou et al, 1998).…”

Section: Introductionmentioning

confidence: 98%

“…Regions of CDC42 and Rac1 required for these and other cellular events have been examined by introducing e ector mutations into activated proteins (Joneson et al, 1996;Lamarche et al, 1996;Westwick et al, 1997). These mutagenesis studies have centered on the region spanning amino acids 26 ± 43 of CDC42 and Rac1.…”

Section: Introductionmentioning

confidence: 99%

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Cellular functions of TC10, a Rho family GTPase: regulation of morphology, signal transduction and cell growth

Murphy

Solski²,

Jillian

et al. 1999

Oncogene

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The small Ras-related GTPase, TC10, has been classi®ed on the basis of sequence homology to be a member of the Rho family. This family, which includes the Rho, Rac and CDC42 subfamilies, has been shown to regulate a variety of apparently diverse cellular processes such as actin cytoskeletal organization, mitogen-activated protein kinase (MAPK) cascades, cell cycle progression and transformation. In order to begin a study of TC10 biological function, we expressed wild type and various mutant forms of this protein in mammalian cells and investigated both the intracellular localization of the expressed proteins and their abilities to stimulate known Rho family-associated processes. Wild type TC10 was located predominantly in the cell membrane (apparently in the same regions as actin ®laments), GTPase defective (75L) and GTP-binding defective (31N) mutants were located predominantly in cytoplasmic perinuclear regions, and a deletion mutant lacking the carboxyl terminal residues required for posttranslational prenylation was located predominantly in the nucleus. The GTPase defective (constitutively active) TC10 mutant: (1) stimulated the formation of long ®lopodia; (2) activated c-Jun amino terminal kinase (JNK); (3) activated serum response factor (SRF)-dependent transcription; (4) activated NF-kB-dependent transcription; and (5) synergized with an activated Rafkinase (Raf-CAAX) to transform NIH3T3 cells. In addition, wild type TC10 function is required for full HRas transforming potential. We demonstrate that an intact e ector domain and carboxyl terminal prenylation signal are required for proper TC10 function and that TC10 signals to at least two separable downstream target pathways. In addition, TC10 interacted with the actin-binding and ®lament-forming protein, pro®lin, in both a two-hybrid cDNA library screen, and an in vitro binding assay. Taken together, these data support a classi®cation of TC10 as a member of the Rho family, and in particular, suggest that TC10 functions to regulate cellular signaling to the actin cytoskeleton and processes associated with cell growth.

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Section: Tc10 Is a Member Of The Rho Family Of Ras-related Gtpasesmentioning

confidence: 69%

Section: Tc10 Is a Member Of The Rho Family Of Ras-related Gtpasesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cellular functions of TC10, a Rho family GTPase: regulation of morphology, signal transduction and cell growth

Murphy

Solski²,

Jillian

et al. 1999

Oncogene

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show abstract

“…On the other hand, cells expressing dominant-negative RhoA (T19N) mutant protein had a much slower proliferation rate due to a longer G1 phase (85% of asynchronous cells in G1) ( Figure 6a). Another small geranylgeranylated GTPase, Rac1, has been implicated in the assembly of the actin cytoskeleton leading to cell proliferation (Joneson et al, 1996;Lamarche et al, 1996) and, thus, could also be a mediator of TRAMP cell growth. In contrast to TRAMP cells that express dominantnegative RhoA (T19N) (Figure 6b)).…”

Section: Microinjection Experiments Have Determined Thatmentioning

confidence: 99%

Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line

et al. 1999

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Prostate cancer cells derived from transgenic mice with adenocarcinoma of the prostate (TRAMP cells) were treated with the HMG-CoA reductase inhibitor, lovastatin. This caused inactivation of the small GTPase RhoA, actin stress ®ber disassembly, cell rounding, growth arrest in the G1 phase of the cell cycle, cell detachment and apoptosis. Addition of geranylgeraniol (GGOL) in the presence of lovastatin, to stimulate protein geranylgeranylation, prevented lovastatin's e ects. That is, RhoA was activated, actin stress ®bers were assembled, the cells assumed a¯at morphology and cell growth resumed. The following observations support an essential role for RhoA in TRAMP cell growth: (1) TRAMP cells expressing dominant-negative RhoA (T19N) mutant protein displayed few actin stress ®bers and grew at a slower rate than controls (35 h doubling time for cells expressing RhoA (T19N) vs 20 h for untransfected cells); (2) TRAMP cells expressing constitutively active RhoA (Q63L) mutant protein displayed a contractile phenotype and grew faster than controls (13 h doubling time). Interestingly, addition of farnesol (FOL) with lovastatin, to stimulate protein farnesylation, prevented lovastatin-induced cell rounding, cell detachment and apoptosis, and stimulated cell spreading to a spindle shaped morphology. However, RhoA remained inactive and growth arrest persisted. The morphological e ects of FOL addition were prevented in TRAMP cells expressing dominant-negative H-Ras (T17N) mutant protein. Thus, it appears that H-Ras is capable of inducing cell spreading, but incapable of supporting cell proliferation, in the absence of geranylgeranylated proteins like RhoA.

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Integrin-type signaling has a distinct influence on NMDA-induced cytoskeletal disassembly

Bahr

2000

J. Neurosci. Res.

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Adhesion responses triggered by integrin-class matrix receptors have been implicated in the synaptic reorganization events necessary for certain types of neuronal plasticity. Hippocampal slice cultures were used to test whether the related structural transformations elicited by NMDA receptor stimulation are regulated by integrin-type signals. Infusing the slices with NMDA for a short period induced the expected disassembly of the cytoskeletal network, measured with antibodies that selectively recognize spectrin cleavage sites targeted by the protease calpain. Marked levels of the 150-kDa breakdown product (BDP) were produced, whereas concentrations of the parent spectrin were not changed. Interestingly, the calpain cleavage events were attenuated by 60% when integrin-type signaling was disrupted with the antagonist Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP). This effect was RGDS-dependent, was largely evident in synapse-dense dendritic areas, particularly in subfield CA1, and was abolished when the NMDA exposure period was >5 min. These findings suggest that only those cytoskeletal alterations associated with brief synaptic activity are regulated by intact contact zones. AMPA-type glutamate receptors also were tested because, like spectrin, they are targets for calpain. Brief NMDA treatment caused a 15% loss of AMPA receptor GluR1 carboxytermini and this modification was augmented to 32% in the presence of GRGDSP. Thus, although blockage of matrix recognition signals decreased spectrin's susceptibility to disassembly, it increased the susceptibility of AMPA receptors to proteolysis. These data indicate that integrin-type signaling complexes are appropriately positioned to govern cytoskeletal reconfiguration while stabilizing the structural nature of AMPA receptors.

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RAC Regulation of Actin Polymerization and Proliferation by a Pathway Distinct from Jun Kinase

Cited by 250 publications

References 26 publications

Cellular functions of TC10, a Rho family GTPase: regulation of morphology, signal transduction and cell growth

Cellular functions of TC10, a Rho family GTPase: regulation of morphology, signal transduction and cell growth

Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line

Integrin-type signaling has a distinct influence on NMDA-induced cytoskeletal disassembly

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