Cellular Control of Cortical Actin Nucleation
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Bibliographic record
Abstract
The contractile actin cortex is a thin layer of actin, myosin, and actin-binding proteins that subtends the membrane of animal cells. The cortex is the main determinant of cell shape and plays a fundamental role in cell division [1Stewart M.P. Helenius J. Toyoda Y. Ramanathan S.P. Muller D.J. Hyman A.A. Hydrostatic pressure and the actomyosin cortex drive mitotic cell rounding.Nature. 2011; 469: 226-230Crossref PubMed Scopus (446) Google Scholar, 2Kunda P. Pelling A.E. Liu T. Baum B. Moesin controls cortical rigidity, cell rounding, and spindle morphogenesis during mitosis.Curr. Biol. 2008; 18: 91-101Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 3Bray D. White J.G. Cortical flow in animal cells.Science. 1988; 239: 883-888Crossref PubMed Scopus (418) Google Scholar], migration [4Cramer L.P. Forming the cell rear first: breaking cell symmetry to trigger directed cell migration.Nat. Cell Biol. 2010; 12: 628-632Crossref PubMed Scopus (84) Google Scholar], and tissue morphogenesis [5Levayer R. Lecuit T. Biomechanical regulation of contractility: spatial control and dynamics.Trends Cell Biol. 2012; 22: 61-81Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. For example, cortex contractility plays a crucial role in amoeboid migration of metastatic cells [6Charras G. Paluch E. Blebs lead the way: how to migrate without lamellipodia.Nat. Rev. Mol. Cell Biol. 2008; 9: 730-736Crossref PubMed Scopus (552) Google Scholar] and during division, where its misregulation can lead to aneuploidy [7Sedzinski J. Biro M. Oswald A. Tinevez J.Y. Salbreux G. Paluch E. Polar actomyosin contractility destabilizes the position of the cytokinetic furrow.Nature. 2011; 476: 462-466Crossref PubMed Scopus (247) Google Scholar]. Despite its importance, our knowledge of the cortex is poor, and even the proteins nucleating it remain unknown, though a number of candidates have been proposed based on indirect evidence [8Eisenmann K.M. Harris E.S. Kitchen S.M. Holman H.A. Higgs H.N. Alberts A.S. Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex.Curr. Biol. 2007; 17: 579-591Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 9Hannemann S. Madrid R. Stastna J. Kitzing T. Gasteier J. Schönichen A. Bouchet J. Jimenez A. Geyer M. Grosse R. et al.The Diaphanous-related Formin FHOD1 associates with ROCK1 and promotes Src-dependent plasma membrane blebbing.J. Biol. Chem. 2008; 283: 27891-27903Crossref PubMed Scopus (59) Google Scholar, 10Kitzing T.M. Wang Y. Pertz O. Copeland J.W. Grosse R. Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC.Oncogene. 2010; 29: 2441-2448Crossref PubMed Scopus (115) Google Scholar, 11Kitzing T.M. Sahadevan A.S. Brandt D.T. Knieling H. Hannemann S. Fackler O.T. Grosshans J. Grosse R. Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion.Genes Dev. 2007; 21: 1478-1483Crossref PubMed Scopus (136) Google Scholar, 12Stastna J. Pan X. Wang H. Kollmannsperger A. Kutscheidt S. Lohmann V. Grosse R. Fackler O.T. Differing and isoform-specific roles for the formin DIAPH3 in plasma membrane blebbing and filopodia formation.Cell Res. 2012; 22: 728-745Crossref PubMed Scopus (20) Google Scholar, 13Derivery E. Fink J. Martin D. Houdusse A. Piel M. Stradal T.E. Louvard D. Gautreau A. Free Brick1 is a trimeric precursor in the assembly of a functional wave complex.PLoS One. 2008; 3: e2462Crossref PubMed Scopus (54) Google Scholar, 14Wyse M.M. Lei J. Nestor-Kalinoski A.L. Eisenmann K.M. Dia-interacting protein (DIP) imposes migratory plasticity in mDia2-dependent tumor cells in three-dimensional matrices.PLoS One. 2012; 7: e45085Crossref PubMed Scopus (16) Google Scholar, 15Tominaga T. Sahai E. Chardin P. McCormick F. Courtneidge S.A. Alberts A.S. Diaphanous-related formins bridge Rho GTPase and Src tyrosine kinase signaling.Mol. Cell. 2000; 5: 13-25Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar]. Here, we used two independent approaches to identify cortical actin nucleators: a proteomic analysis using cortex-rich isolated blebs, and a localization/small hairpin RNA (shRNA) screen searching for phenotypes with a weakened cortex or altered contractility. This unbiased study revealed that two proteins generated the majority of cortical actin: the formin mDia1 and the Arp2/3 complex. Each nucleator contributed a similar amount of F-actin to the cortex but had very different accumulation kinetics. Electron microscopy examination revealed that each nucleator affected cortical network architecture differently. mDia1 depletion led to failure in division, but Arp2/3 depletion did not. Interestingly, despite not affecting division on its own, Arp2/3 inhibition potentiated the effect of mDia1 depletion. Our findings indicate that the bulk of the actin cortex is nucleated by mDia1 and Arp2/3 and suggest a mechanism for rapid fine-tuning of cortex structure and mechanics by adjusting the relative contribution of each nucleator.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it