Profilin: At the crossroads of signal transduction and the actin cytoskeleton

Sohn, Richard H.; Goldschmidt‐Clermont, Pascal J.

doi:10.1002/bies.950160705

Cited by 172 publications

(128 citation statements)

References 66 publications

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“…Such a protein is pro®lin (see Results). Pro®lin is a small protein (140 amino acids) that localizes in vivo with dynamic actin ®laments (Buû et al, 1992;Rothkegel et al, 1996), binds and sequesters globular actin (G actin) in vitro, and functions to promote actin ®lament and microspike formation in vivo (for review of pro®lin function see Sohn and Goldschmidt-Clermont, 1994;Reinhard et al, 1995;Suetsugu et al, 1998). The interaction of TC10 with pro®lin may provide valuable insights into mechanisms linking cytoskeletal rearrangements to the Rho family.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Originally identified as an actin-monomer sequestering protein, profilin was subsequently shown to enhance the rate of nucleotide exchange on actin and to retard the rate of hydrolysis of bound ATP [1,2]. Profilin also irtteracts with the acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) in vitro, which has the combined effects of blocking profilin-actin interactions and preventing PIP2 cleavage by unphosphorylated (unactivated) phospholipase C'fl [3][4][5][6].…”

Section: Yeast Strains and Culture Conditionsmentioning

confidence: 99%

Profilin is required for the normal timing of actin polymerization in response to thermal stress

Yeh

Haarer

1996

FEBS Letters

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We have used a fluorometric assay to determine the relative amounts of polymerized actin (F-actin) in wild-type and profilin mutant yeast cells. Our results indicate that profilin plays a role in maintaining normal F-actin levels in response to shifts to high temperature. Cells lacking prof'din display a greater drop in F-actin levels upon such temperature shifts, and are slower to recover to initial F-actin levels than are wild-type cells. Interestingly, shifts to cold temperatures result in rapid increases of F-actin levels in wild-type and profilin null cells. We have further determined that shifting to high-osmolarity growth conditions causes a relatively slow decrease in F-actin levels in wild-type cells, and a small but rapid increase in the F-actin levels in profilin null cells. Profilin null cells contain normal concentrations of F-actin while growing exponentially at room temperature, indicating that profilin is not essential for maintaining F-actin concentrations during steady-state growth. Our data suggest that actin is inherently unstable in vivo at high temperatures, and that profilin helps to maintain actin in its filamentous state at these temperatures, perhaps by stimulating actin polymerization in a proper temporal and spatial fashion. direct interaction between yeast profilin and adenylate cyclase (S. Palmieri and B. Haarer, unpublished data).Despite these many interactions attributed to profilins from various species, it is still unclear which roles are central to profilin function, and how such properties relate to the in vivo control of the actin cytoskeleton. Convincing arguments can be made for an in vivo role as an inhibitor [13][14][15], or stimulator [8,16] of actin polymerization. Indeed, it is entirely likely that profilin could be playing both roles, depending on species, cell type, or temporal regulation within an individual cell. To further address profilin's potential in vivo functions, we have utilized a fluorometric assay to measure the relative filamentous actin content in cells before and after changing growth conditions. Our findings are consistent with profilin's playing a significant role in the stimulation of actin polymerization under conditions that are perturbing to the yeast actin cytoskeleton. Materials and methods

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“…Generally, the data obtained from cells with different profilin levels are in harmony with the notion that in lower eukaryotes the central role of profilin is to sequester G-actin, whereas in higher eukaryotes this is mainly done via other G-actin binding proteins such as thymosin 4 (Safer et al, 1991), and profilins are mostly implicated in the actin filament dynamics control (Sohn & Goldschmidt-Clermont, 1994). …”

Section: Profilin Actin and Cytoskeletonmentioning

confidence: 56%

“…In vivo, the global view that the main biological function of profilin was observed in its actin sequestering effect became debatable, principally due to the finding that the concentration of profilin in cells and its actin-binding affinity are inadequate to stabilize the G-actin pool (Babcock & Rubenstein 1993;Goldschmidt-Clermont et al, 1991;Machesky & Pollard, 1993;Sohn & Goldschmidt-Clermont, 1994). Generally, the data obtained from cells with different profilin levels are in harmony with the notion that in lower eukaryotes the central role of profilin is to sequester G-actin, whereas in higher eukaryotes this is mainly done via other G-actin binding proteins such as thymosin 4 (Safer et al, 1991), and profilins are mostly implicated in the actin filament dynamics control (Sohn & Goldschmidt-Clermont, 1994).…”

Section: Profilin Actin and Cytoskeletonmentioning

confidence: 99%