Mechano-chemical feedbacks regulate actin mesh growth in lamellipodial protrusions.
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.
Hu
Longhua
L
Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina, USA.
Papoian
Garegin A
GA
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*
D051344:Actin Capping Proteins; D051376:Actin-Related Protein 2-3 Complex; D000199:Actins
Proc Natl Acad Sci U S A. 1998 May 26;95(11):6181-6
9600938
Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18926-31
16361441
Biophys J. 1993 Jul;65(1):316-24
8369439
Biophys J. 2006 Jan 15;90(2):454-69
16239328
Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):4906-11
16549794
J Math Biol. 2009 Jan;58(1-2):105-34
18461331
Biophys J. 2003 May;84(5):2907-18
12719223
Nat Cell Biol. 2007 Oct;9(10):1110-21
17909522
J Chem Phys. 2006 Oct 21;125(15):154901
17059287
Biophys J. 2008 May 15;94(10):3839-52
18234810
Biophys J. 2001 Dec;81(6):3116-36
11720979
Annu Rev Biophys. 2008;37:65-95
18573073
Cell. 2008 May 30;133(5):841-51
18510928
Nature. 1999 Oct 7;401(6753):613-6
10524632
Biophys J. 2008 Aug;95(3):1393-411
18390606
J Biol Chem. 2009 Feb 27;284(9):5433-7
18940808
Science. 2001 May 25;292(5521):1502-6
11379633
Multiscale Model Simul. 2005;3(2):413-439
19116671
Biophys J. 2007 Dec 1;93(11):3798-810
17704150
Cell. 2005 Jul 29;122(2):169-82
16051143
Nature. 2004 Apr 1;428(6982):574-8
15058306
J Biol Chem. 2008 Mar 14;283(11):7135-44
18165685
J Mol Biol. 1997 Jun 20;269(4):459-67
9217250
Biophys J. 2002 Sep;83(3):1237-58
12202352
Nature. 2008 May 22;453(7194):475-80
18497816
Annu Rev Biophys Biomol Struct. 2007;36:451-77
17477841
Phys Rev Lett. 2007 Apr 20;98(16):168103
17501468
Genetics. 2004 May;167(1):523-30
15166174
Cell. 2003 Feb 21;112(4):453-65
12600310
Biophys J. 2001 Oct;81(4):1907-23
11566765
Biophys J. 2009 May 6;96(9):3529-42
19413959
Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11570-5
19556544
Phys Rev Lett. 2007 Jun 1;98(22):228301
17677882
J Cell Biol. 1999 May 31;145(5):1009-26
10352018
Curr Opin Cell Biol. 2009 Feb;21(1):28-37
19168341
Cell. 2002 May 17;109(4):509-21
12086607
Cell. 1996 Feb 9;84(3):359-69
8608589
J Chem Phys. 2006 Sep 28;125(12):124106
17014165
Phys Rev Lett. 2007 Aug 3;99(5):058103
17930797
Biophys J. 2004 Feb;86(2):1074-81
14747342
Curr Opin Cell Biol. 2006 Feb;18(1):32-9
16318917
Nature. 1991 Jul 11;352(6331):126-31
2067574
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2374-9
12606710
Bull Math Biol. 2006 Jul;68(5):1169-211
16794915
Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7086-91
17440042
Cell. 2008 May 30;133(5):765-7
18510919
Biophys J. 2005 Nov;89(5):3589-602
16085776
PLoS Biol. 2007 Sep;5(9):e233
17760506
Biophys J. 2008 Nov 15;95(10):4529-39
18708451
Biophys J. 2008 Dec 15;95(12):5508-23
18708450