Conversion of mechanical force into biochemical signaling.
Physical forces play important roles in regulating cell proliferation, differentiation, and death by activating intracellular signal transduction pathways. How cells sense mechanical stimulation, however, is largely unknown. Most studies focus on cellular membrane proteins such as ion channels, integrins, and receptors for growth factors as mechanosensory units. Here we show that mechanical stretch-induced c-Src protein tyrosine kinase activation is mediated through the actin filament-associated protein (AFAP). Distributed along the actin filaments, AFAP can directly active c-Src through binding to its Src homology 3 and/or 2 domains. Mutations at these specific binding sites on AFAP blocked mechanical stretch-induced c-Src activation. Therefore, mechanical force can be transmitted along the cytoskeleton, and interaction between cytoskeletal associated proteins and enzymes related to signal transduction may convert physical forces into biochemical reactions. Cytoskeleton deformation-induced protein-protein interaction via specific binding sites may represent a novel intracellular mechanism for cells to sense mechanical stimulation.
Han
Bing
B
Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada.
Bai
Xiao-Hui
XH
Lodyga
Monika
M
Xu
Jing
J
Yang
Burton B
BB
Keshavjee
Shaf
S
Post
Martin
M
Liu
Mingyao
M
D000818:Animals; D001665:Binding Sites; D001696:Biomechanical Phenomena; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D002645:Chickens; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology* / Q000648:ultrastructure; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology; D041681:NIH 3T3 Cells; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D019061:src-Family Kinases
C497360:AFAP1 protein, human; D003598:Cytoskeletal Proteins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; C485192:green fluorescent protein, Aequorea victoria; D049452:Green Fluorescent Proteins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human