Publication Date:
2011-09-20
Description:
Mechanical stresses elicit cellular reactions mediated by chemical signals. Defective responses to forces underlie human medical disorders such as cardiac failure and pulmonary injury. The actin cytoskeleton's connectivity enables it to transmit forces rapidly over large distances, implicating it in these physiological and pathological responses. Despite detailed knowledge of the cytoskeletal structure, the specific molecular switches that convert mechanical stimuli into chemical signals have remained elusive. Here we identify the actin-binding protein filamin A (FLNA) as a central mechanotransduction element of the cytoskeleton. We reconstituted a minimal system consisting of actin filaments, FLNA and two FLNA-binding partners: the cytoplasmic tail of beta-integrin, and FilGAP. Integrins form an essential mechanical linkage between extracellular and intracellular environments, with beta-integrin tails connecting to the actin cytoskeleton by binding directly to filamin. FilGAP is an FLNA-binding GTPase-activating protein specific for RAC, which in vivo regulates cell spreading and bleb formation. Using fluorescence loss after photoconversion, a novel, high-speed alternative to fluorescence recovery after photobleaching, we demonstrate that both externally imposed bulk shear and myosin-II-driven forces differentially regulate the binding of these partners to FLNA. Consistent with structural predictions, strain increases beta-integrin binding to FLNA, whereas it causes FilGAP to dissociate from FLNA, providing a direct and specific molecular basis for cellular mechanotransduction. These results identify a molecular mechanotransduction element within the actin cytoskeleton, revealing that mechanical strain of key proteins regulates the binding of signalling molecules.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204864/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204864/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ehrlicher, A J -- Nakamura, F -- Hartwig, J H -- Weitz, D A -- Stossel, T P -- R01 HL019429/HL/NHLBI NIH HHS/ -- R01 HL019429-36/HL/NHLBI NIH HHS/ -- R01 HL19429/HL/NHLBI NIH HHS/ -- T32 HL007680/HL/NHLBI NIH HHS/ -- T32 HL007680-20/HL/NHLBI NIH HHS/ -- T32 HL07680/HL/NHLBI NIH HHS/ -- England -- Nature. 2011 Sep 18;478(7368):260-3. doi: 10.1038/nature10430.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21926999" target="_blank"〉PubMed〈/a〉
Keywords:
Actin Cytoskeleton/chemistry/metabolism
;
Actins/chemistry/*metabolism
;
Animals
;
Binding Sites
;
Contractile Proteins/*metabolism
;
Filamins
;
Fluorescence
;
GTPase-Activating Proteins/*metabolism
;
Humans
;
Integrin beta Chains/*metabolism
;
Ligands
;
Mechanotransduction, Cellular/*physiology
;
Microfilament Proteins/*metabolism
;
Myosin Type II/metabolism
;
Protein Binding
;
Rabbits
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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