title: Mechano-chemical feedbacks regulate actin mesh growth in lamellipodial protrusions.
abstract: During cell motion on a substratum, eukaryotic cells project sheetlike lamellipodia which contain a dynamically remodeling three-dimensional actin mesh. A number of regulatory proteins and subtle mechano-chemical couplings determine the lamellipodial protrusion dynamics. To study these processes, we constructed a microscopic physico-chemical computational model, which incorporates a number of fundamental reaction and diffusion processes, treated in a fully stochastic manner. Our work sheds light on the way lamellipodial protrusion dynamics is affected by the concentrations of actin and actin-binding proteins. In particular, we found that protrusion speed saturates at very high actin concentrations, where filament nucleation does not keep up with protrusion. This results in sparse filamentous networks, and, consequently, high resistance forces on individual filaments. We also observed maxima in lamellipodial growth rates as a function of Arp2/3, a nucleating protein, and capping proteins. We provide detailed physical explanations behind these effects. In particular, our work supports the actin-funneling-hypothesis explanation of protrusion speed enhancement at low capping protein concentrations. Our computational results are in agreement with a number of related experiments. Overall, our work emphasizes that elongation and nucleation processes work highly cooperatively in determining the optimal protrusion speed for the actin mesh in lamellipodia.
authors.affiliation: Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Longhua
authors.initials: L
authors.lastname: Hu
authors.forename: Garegin A
authors.initials: GA
authors.lastname: Papoian
mesh_terms: D051344:Actin Capping Proteins / Q000378:metabolism; D008841:Actin Cytoskeleton / Q000378:metabolism; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D025461:Feedback, Physiological; D008954:Models, Biological; D009068:Movement; D011554:Pseudopodia / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051344:Actin Capping Proteins; D051376:Actin-Related Protein 2-3 Complex; D000199:Actins
references.citation: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6181-6
references.pmid: 9600938
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18926-31
references.pmid: 16361441
references.citation: Biophys J. 1993 Jul;65(1):316-24
references.pmid: 8369439
references.citation: Biophys J. 2006 Jan 15;90(2):454-69
references.pmid: 16239328
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):4906-11
references.pmid: 16549794
references.citation: J Math Biol. 2009 Jan;58(1-2):105-34
references.pmid: 18461331
references.citation: Biophys J. 2003 May;84(5):2907-18
references.pmid: 12719223
references.citation: Nat Cell Biol. 2007 Oct;9(10):1110-21
references.pmid: 17909522
references.citation: J Chem Phys. 2006 Oct 21;125(15):154901
references.pmid: 17059287
references.citation: Biophys J. 2008 May 15;94(10):3839-52
references.pmid: 18234810
references.citation: Biophys J. 2001 Dec;81(6):3116-36
references.pmid: 11720979
references.citation: Annu Rev Biophys. 2008;37:65-95
references.pmid: 18573073
references.citation: Cell. 2008 May 30;133(5):841-51
references.pmid: 18510928
references.citation: Nature. 1999 Oct 7;401(6753):613-6
references.pmid: 10524632
references.citation: Biophys J. 2008 Aug;95(3):1393-411
references.pmid: 18390606
references.citation: J Biol Chem. 2009 Feb 27;284(9):5433-7
references.pmid: 18940808
references.citation: Science. 2001 May 25;292(5521):1502-6
references.pmid: 11379633
references.citation: Multiscale Model Simul. 2005;3(2):413-439
references.pmid: 19116671
references.citation: Biophys J. 2007 Dec 1;93(11):3798-810
references.pmid: 17704150
references.citation: Cell. 2005 Jul 29;122(2):169-82
references.pmid: 16051143
references.citation: Nature. 2004 Apr 1;428(6982):574-8
references.pmid: 15058306
references.citation: J Biol Chem. 2008 Mar 14;283(11):7135-44
references.pmid: 18165685
references.citation: J Mol Biol. 1997 Jun 20;269(4):459-67
references.pmid: 9217250
references.citation: Biophys J. 2002 Sep;83(3):1237-58
references.pmid: 12202352
references.citation: Nature. 2008 May 22;453(7194):475-80
references.pmid: 18497816
references.citation: Annu Rev Biophys Biomol Struct. 2007;36:451-77
references.pmid: 17477841
references.citation: Phys Rev Lett. 2007 Apr 20;98(16):168103
references.pmid: 17501468
references.citation: Genetics. 2004 May;167(1):523-30
references.pmid: 15166174
references.citation: Cell. 2003 Feb 21;112(4):453-65
references.pmid: 12600310
references.citation: Biophys J. 2001 Oct;81(4):1907-23
references.pmid: 11566765
references.citation: Biophys J. 2009 May 6;96(9):3529-42
references.pmid: 19413959
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11570-5
references.pmid: 19556544
references.citation: Phys Rev Lett. 2007 Jun 1;98(22):228301
references.pmid: 17677882
references.citation: J Cell Biol. 1999 May 31;145(5):1009-26
references.pmid: 10352018
references.citation: Curr Opin Cell Biol. 2009 Feb;21(1):28-37
references.pmid: 19168341
references.citation: Cell. 2002 May 17;109(4):509-21
references.pmid: 12086607
references.citation: Cell. 1996 Feb 9;84(3):359-69
references.pmid: 8608589
references.citation: J Chem Phys. 2006 Sep 28;125(12):124106
references.pmid: 17014165
references.citation: Phys Rev Lett. 2007 Aug 3;99(5):058103
references.pmid: 17930797
references.citation: Biophys J. 2004 Feb;86(2):1074-81
references.pmid: 14747342
references.citation: Curr Opin Cell Biol. 2006 Feb;18(1):32-9
references.pmid: 16318917
references.citation: Nature. 1991 Jul 11;352(6331):126-31
references.pmid: 2067574
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2374-9
references.pmid: 12606710
references.citation: Bull Math Biol. 2006 Jul;68(5):1169-211
references.pmid: 16794915
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7086-91
references.pmid: 17440042
references.citation: Cell. 2008 May 30;133(5):765-7
references.pmid: 18510919
references.citation: Biophys J. 2005 Nov;89(5):3589-602
references.pmid: 16085776
references.citation: PLoS Biol. 2007 Sep;5(9):e233
references.pmid: 17760506
references.citation: Biophys J. 2008 Nov 15;95(10):4529-39
references.pmid: 18708451
references.citation: Biophys J. 2008 Dec 15;95(12):5508-23
references.pmid: 18708450