生物體內多數的器官均是軟的，基質的軟硬度是調控細胞功能與行為很重要的原因，且機械力的刺激在發育或癌化的過程均十分重要。然而，細胞如何感應外界物理環境仍然尚未明瞭。本論文的目的欲瞭解細胞如何感應其外界物理環境。總共有兩部分的實驗包含於本論文中：(1)欲釐清細胞機械力感受器的組成成分並分析其作用機轉；(2)欲探討低硬度的膠原蛋白凝膠如何修飾傳統integrin所調控的細胞行為。
本論文的第一部份顯示，相對於培養在高硬度的環境下，當細胞培養在低硬度的膠原蛋白凝膠中展現較高的移行能力。低硬度膠原蛋白凝膠誘發延遲但持續的ERK1/2磷酸化。利用抑制劑抑制ERK磷酸化或是無活性的ERK均使得細胞無法攤開且其在膠原蛋白凝膠上的移行也被抑制。有趣的是，這些磷酸化的ERK1/2分佈在focal adhesion和lipid raft的位置。利用lipid raft的抑制劑M刍CD可以抑制膠原蛋白凝膠所誘發的ERK1/2磷酸化及移行。大量表現FRNK促使ERK1/2磷酸化。同時，低基質軟硬度誘發FAK降解成一個35kD的片段。利用Calpain 抑制劑阻止FAK降解能抑制低硬度基質所導致的ERK磷酸化，而MbCD卻無此功效。綜合來說，本實驗證明了，低硬度的膠原蛋白凝膠誘發FAK降解，而此降解片段能進而誘發ERK1/2磷酸化，並透由lipid raft來促進細胞攤開及移行。
本論文第二部份的研究結果顯示，低硬度的膠原蛋白凝膠藉由延緩lipid raft分佈而降低b1 integrin活化，聚集，以及FAKY397磷酸化。此外，過度表現自發聚集的b1 integrin (V737N) 可以提高FAKY397在低硬度基質上的磷酸化程度，而持續活化的b1 integrin (G429N) 則無此作用。利用螢光共振能量轉移(FRET) 測量b1 integrin在不同軟硬度基質上的聚集程度時發現，在軟硬度為58-386 Pa的基質上時，b1 integrin 的聚集程度與基質軟硬度成正比。而此一現象是透過actin而非microtubule調控。另外，增加b1 integrin聚集程度同時增加了b1 integrin, FAK, talin之間的作用。
總結以上的研究，本論文對於細胞或組織如何感應其外界物理環境之機制有深入闡明。

Most organs are soft, and the likely reason is that substratum rigidity plays important roles in regulation of cellular functions and behaviors. Mechanical stimuli are essential during development and tumorigenesis. However, how cells sense their physical environment has not been fully explored. The aim of this thesis is to understand how cells sense their physical environment. Two parts in this study are included: (1) to investigate whether and how low substratum rigidity of collagen gel modifies canonical integrin-mediated cellular behavior, and (2) to delineate the mechanosensing machinery and its mode of action for cells at substratum rigidity of soft tissue range.
The fisrt part of this thesis showed that cells cultured on collagen gel exhibited higher migration capacity than those cultured on collagen gel-coated dishes. Low rigidity of collagen gel induced delayed but persistent phosphorylation of ERK1/2. Inhibition of collagen gel-induced ERK1/2 phosphorylation by MEK inhibitors or ERK2 kinase mutant induced a rounding up of the cells and prevented collagen gel-induced cell migration. Interestingly, phosphorylated ERK1/2 induced by low rigidity was present in focal adhesion sites and the lipid rafts. MbCD (Methyl-b-cyclodextrin), a lipid raft inhibitor, inhibited collagen gel-induced ERK1/2 phosphorylation and cell migration. Overexpression of FAK C-terminal fragment (FRNK) triggered ERK phosphorylation in MDCK cells. Meanwhile, low substratum rigidity induced degradation of FAK into a 35kDa C-terminal fragment. A calpain inhibitor that partially rescued FAK degradation also prevented low rigidity-induced ERK phosphorylation. However, MbCD did not prevent low rigidity-induced FAK degradation. Taken together, we demonstrate that the degradation product of FAK induced by collagen gel triggers activation of ERK1/2, which in turn facilitates cell spreading and migration through the lipid raft.
The second part of this thesis showed that low rigidity of collagen gel down-regulates b1 integrin activation, clustering and FAKY397 phosphorylation, which is mediated by delayed raft externalization. Moreover, overexpression of auto-clustered b1 integrin (V737N) but not constitutively active b1 integrin (G429N) rescues FAKY397 phosphorylation level suppressed by low substratum rigidity. Using fluorescence resonance energy transfer (FRET) to assess b1 integrin clustering, we have found that substratum rigidity between 58-386 pascal (Pa) triggers b1 integrin clustering in a dose-dependent manner, which is highly dependent on actin filaments but not microtubules. Furthermore, augmentation of b1 integrin clustering enhances the interaction between b1 integrin, FAK and talin. Taken together, our findings provide a new insight into how soft tissues sense their physical environment and the mode of action.
In conclusion, this thesis provides the key to understand the fundamental mechanisms in how cells interact with physical environment.

Akimov SA, Kuzmin PI, Zimmerberg J, Cohen FS (2007) Lateral tension increases the line tension between two domains in a lipid bilayer membrane. Phys. Rev. E. Stat. Nonlin. Sof Matter. Phys. E75: 011919
Almeida-Silveira MI, Lambertz D, Perot C, Goubel F (2000) Changes in stiffness induced by hindlimb suspension in rat Achilles tendon. Eru. J. Appl. Physiol. 81: 252-257
Arcangeli A, Becchetti A (2006) Complex functional interaction between integrin receptors and ion channels. Trends Cell Biol. 16: 631-639
Arthur JS, Crawford C (1996) Investigation of the interaction of m-calpain with phospholipids: calpain-phospholipid interactions. Biochim. Biophys. Acta. 1293: 201-206
Bae U, Dighe M, Dubinsky T, Minoshima S, Shamdasani V, Kim Y (2007) Ultrasound thyroid elastography using carotid artery pulsation. J. Ultrasound Med. 26: 797-805
Balasubramanian N, Scott DW, Castle JD, Casanova JE, Schwartz MA (2007) Arf6 and microtubules in adhesion-dependent trafficking of lipid rafts. Nat. Cell Biol. 9: 1381-1391
Bershadsky AD, Balaban NQ, Geiger B (2003) Adhesion-dependent cell mechanosensitivity. Annu. Rev. Cell Dev. Biol. 19: 677-695
Bhadriraju K, Hansen LK (2002) Extracellular matris- and cytoskeleton-dependent changes in cell shape and stiffness. Exp. Cell Res. 278: 92-100
Calalb MB, Polte TR, Hanks SK (1995) Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. Mol. Cell. Biol. 15: 954-963
Calderwood DA (2004) Talin controls integrin activation. Biochem. Soc. Trans. 32: 434-437
Carragher NO, Levkau B, Ross R, Raines EW (1999) Degraded collagen fragments promote rapid disassembly of smooth muscle focal adhesions that correlates with cleavage of pp125(FAK), paxillin, and talin. J. Cell Biol. 147: 619-630
Carragher NO, Westhoff MA, Fincham VJ, Schaller MD, Frame MC (2003) A novel role for FAK as a protease-targeting adaptor protein: regulation by p42 ERK and Src. Curr. Biol. 13: 1442-1450
Carter DR, Beaupre GS, Wong M, Smith RL, Andriacchi TP, Schurman DJ (2004) The mechanobiology of articular cartilage development and degeneration. Clin. Orthop. Relat. Res. 427: S69-S77
Cary LA, Chang JF, Guan JL (1996) Stimulation of cell migration by overexpression of focal adhesion kinase and its association with Src and Fyn. J. Cell Sci. 109: 1787-1794
Cavalcante FSA, Ito S, Brewer K, Sakai H, Alencar AM, Almeida MP, Andrade JS, Majumdar A, Ingenito EP, Suki B (2005) Mechanical interactions between collagen and proteoglycans: implications for the stability of lung tissue. J. Appl. Physiol. 98: 672-279
Chan RW (2004) Measurements of vocal fold tissue viscoelasticity: approaching the male phonatory frequency range. A. Acoust. Soc. Am. 115: 3161-3170
Chatziantoniou C, Dussaule JC (2005) Insights into the mechanism of renal fibrosis: is it possible to achieve regression? Am. J. Physiol. Renal Physiol. 289: F227-F234
Chen CS, Mrksich M, Huang S, Whitesides GM, Ingber DE (1997) Geometric control of cell life and death. Science 276: 1425-1428
Chen H, Choudhury DM, Craig SW (2006) Coincidence of actin filaments and talin is required to activate vinculin. J. Biol. Chem. 281: 40389-40398
Chen HC, Appeddu PA, Isoda H, Guan JL (1996) Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. J. Biol. Chem. 271: 26329-26334
Chiu WT, Wang YH, Tang MJ, Shen MR (2007) Soft substrate induces apoptosis by the disturbance of Ca2+ homeostasis in renal epithelial LLC-PK1 cells. J. Cell. Physiol. 212: 401-410
Chiu WT, Tang MJ, Jao HC, Shen MR (2008) Soft substrate upregulates the interaction of STIM1 with store-operated Ca2+ channels that lead to normal epithelial cell apoptosis. Mol. Biol. Cell 19: 2220-2230
Choquet D, Felsenfeld DP, Sheetz MP (1997) Extracellular matrix rigidity causes strengthening of integrin-cytoskeleton linkages. Cell 88: 39-48
Clark EA, Brugge JS (1995) Integrins and signal transduction pathways: the road taken. Science 268: 233-239
Cluzel C, Saltel F, Lussi J, Paulhe F, Imhof BA, Wehrle-Haller B (2006) The mechanisms and dynamics of avb3 integrin clustering in living cells. J. Cell. Biol. 171: 383-392
Cohen LA, Guan JL (2005) Residues within the first subdomain of the FERM-like domain in focal adhesion kinase are important in its regulation. J. Biol. Chem. 280: 8197-8207
Cooper LA, Shen TL, Guan JL (2003) Regulation of focal adhesion kinase by its amino-terminal domain through an autoinhibitory interaction. Mol. Cell. Biol. 23: 8030-8041.
Cukierman E, Pankov R, Stevens DR, Yamada KM (2001) Taking cell-matrix adhesions to the third dimension. Science 294: 1708-1712
Cukierman E, Pankov R, Stevens DR, Yamada KM (2001) Taking cell-matrix adhesions to the third dimension. Science 294: 1708-1712
Dailey SH, Tateya I, Montequin D, Welham N, Goodyer E. (2004) Viscoelastic measurements of vocal folds using the linear skin rheometer. J. Voice Epub ahead
Danilov YN, Juliano RL (1989) Phorbol ester modulation of integrin-mediated cell adhesion: a postreceptor event. J. Cell Biol. 108: 1925-1933
del Pozo MA, Alderson NB, Kiosses WB, Chiang HH, Anderson RG, Schwartz MA (2004) Integrins regulate Rac targeting by internalization of membrane domain. Science 303: 839-842
Deroanne CF, Lapiere CM, Nusgens BV (2001) In vitro tubulogenesis of endothelial cells by relaxation of the coupling extracellular matrix-cytoskeleton. Cardiovasc. Res. 49: 647-658
Discher DE, Janmey P, Wang YL (2005) Tissue cells feel and respond to the stiffness of their substrate. Science 310: 1139-1143
Dolhnikoff M, Mauad T, Ludwig MS (1999) Extracellular matrix and oscillatory mechanics of rat lung parenchyma in bleomycin-induced fibrosis. Am. J. Respir. Crit. Care Med. 160: 1750-1757
Domke J, Parak WJ, George M, Gaub HE, Radmacher M (1999) Mapping the mechanical pulse of single cardiomyocytes with the atomic force microscope. Eur. Biophys. J. 28: 179-186
Dransfield I, Cabanas C, Craig A, Hogg N (1992) Divalent cation regulation of the function of the leukocyte integrin LFA-1. J. Cell Biol. 116: 219-226
Dykstra M, Cherukuri A, Shon HW, Tzeng SJ, Pierce SK (2003) Location is everything: lipid rafts and immune cell signaling. Annu. Rev. Immunol. 21: 457-481
Eblen ST, Slack JK, Weber MJ, Catling AD (2002) Rac-PAK signaling stimulates extracellular signal-regulated kinase (ERK) activation by regulating formation of MEK1-ERK complexes. Mol. Cell Biol. 22: 6023-6033
Echarri A, Muriel O, Del Pozo MA (2007) Intracellular trafficking of raft/caveolae domains: Insights from integrins signaling. Semin. Cell Dev. Biol. 18: 627-637
Elder SH, Goldstein SA, Kimura JH, Soslowsky LJ, Spengler DM (2001) Chondrocyte differentiation is modulated by frequency and duration of cyclic compressive loading. Ann. Biomed. Eng. 29: 476-482
Emelianov SY, Lubinski MA Skovoroda AR, Erkamp RQ, Leavey SF, Wiggins RC, O’Donnell M (2000) Reconstructive ultrasound elasticity imaging for renal transplant diagnosis: kidney ex vivo results. Ultrason. Imaging 22: 178-194
Engler AJ, Bacakova L, Newman C, Hategan A, Griffin M, Discher DE (2004) Substrate compliance versus ligand density in cell on gel responses. Biophys. J. 86: 617-628
Engler AJ, Griffin MA, Sen S, Bonnemann CG, Sweeney HL, Discher DE (2004) Myotubes differentiate optimally on substrates with tissue-like stiffness: pathological implications for soft or stiff microenvironments. J. Cell Biol. 166: 877-887
Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126: 677-689
Enomoto DNH, Mekkes JR, Bossuyt PMM, Hoekzema R, Bos JD (1996) Quantification of cutaneous sclerosis with a skin elasticity meter in patients with generalized scleroderma. J. Am. Acad. Dermatol. 35: 381-387
Estes BT, Gimble JM, Guilak F (2004) Mechanical signals as regulators of stem cell fate. Curr. Top. Dev. Biol. 60: 91-126
Felsenfeld DP, Schwartzberg PL, Venegas A, Tse R, Sheetz MP (1999) Selective regulation of integrin-cytoskeleton interactions by the tyrosine kinase Src. Nat. Cell Biol. 1: 200-206
Fernandex C, Clark K, Burrows L, Schofield NR, Humphries MJ (1998) Regulation of the extracellular ligand binding activity of integrins. Front. Biosci. 3: d684-d700
Fiford RJ, Bilston LE (2005) The mechanical properties of rat spinal cord in vitro. J. Biomech. 38: 1509-1515
Fincham VJ, James M, Frame MC, Winder SJ (2000) Active ERK/MAP kinase is targeted to newly forming cell-matrix adhesion by integrin engagement and v-Src. EMBO. J. 19: 2911-2923
Flanagan LA, Ju YE, Marg B, Osterfield M, Janmey PA (2002) Neurite branching on deformable substrates. Neuroreport 13: 2411-2415
Freed LE, Langer R, Martin I, Pellis NR, Vunjak-Novakovic G (1997) Tissue engineering of cartilage in space. Proc. Natl. Acad. Sci. USA 94: 13885-13890
Galbraith CG, Yamada KM, Sheetz MP (2002) The relationship between force and focal complex development. J. Cell Biol. 159: 695-705
Garcia-Saez AJ, Chiantia S, Schwille P (2007) Effect of line tension on the lateral organization of lipid membranes. J. Biol. Chem. 282: 33537-33544
Garra BS (2007) Imaging and estimation of tissue elasticity by ultrasound. Ultrasound Q. 23: 255-268
Geiger B, Bershadsky A, Pankov R, Yamada KM (2001) Transmembrane crosstalk between the extracellular matrix-cytoskeleton crosstalk. Nat. Rev. Mol. Cell Biol. 2: 793-805
Geiger B, Bershadsky A (2002) Exploring the neighborhood: Adhesion coupled cell mechanosensors. Cell 110: 139-142
Genes NG, Rowley JA, Mooney DJ, Bonassar LJ (2004) Effect of substrate mechanics on chondrocyte adhesion to modified alginate surfaces. Arch. Biochem. Biophys. 422: 161-167
Georges PC, Hui JJ, Gombos Z, McCormick ME, Wang AY, Uemura M, Mick R, Janmey PA, Furth EE, Wells RG (2007) Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am. J. Physiol. Gastrointest. Lover Physiol. 293: G1147-G1154
Georges PC, Janmey PA (2005) Cell type-specific response to growth on soft materials. J. Appl. Physiol. 98:1547-1553
Giancotti FG, Ruoslahti E (1999) Integrin signaling. Science 285:1028-1032
Giannone G, Jiang G, Sutton DH, Critchley DR, Sheetz MP (2003) Talin1 is critical for force-dependent reinforcement of initial integrin-cytoskeleton bonds but not tyrosine kinase activation. J. Cell. Biol. 163: 409-419
Giannone G, Sheetz MP (2006) Substrate rigidity and force define form through tyrosine phosphatase and kinase pathways. Trends Cell Biol. 16: 213-223
Ginsberg MH, Partridge A, Shattil SJ (2005) Integrin regulation. Curr. Opin. Cell Biol. 17: 509-516
Grzesiak JJ, Davis GE, Kirchhofer D, Pierschbacher MD (1992) Regulation of a2b1-mediated fibroblast migration on type I collagen by shifts in the concentrations of extracellular Mg2+ and Ca2+. J. Cell Biol. 117: 1109-1117
Guan JL (1997a) Role of focal adhesion kinase in integrin signaling. Int. J. Biochem. Cell biol. 29: 1085-1096
Guan JL (1997b) Focal adhesion kinase in integrin signaling. Matrix Biol. 16: 195-200
Guo WH, Frey MT, Burnham NA, Wang YL (2006) Substrate rigidity regulates the formation and maintenance of tissues. Biolphys. J. 90: 2213-2220
Hall TJ, Zhu Y, Spalding CS (2003) In vivo real-time freehand palpation imaging. Ultrasound in Med. & Biol. 29: 427-435
Hamill OP, Martinac B (2001) Molecular basis of mechanotransduction in living cells. Physiol. Rev. 81: 685-740
Han DC, Guan JL (1999) Association of focal adhesion kinase with Grb7 and its role in cell migration. J. Biol. Chem. 274: 24425-24430
Hanzal-Bayer MF, Hancock JF (2007) Lipid rafts and membrane traffic. FEBS Lett. 581: 2098-2104
Hartfield PJ, Greaves MW, Camp DR (1993) b1 integrin-mediated adhesion is regulated by calcium ionophores and endoplasmic reticulum Ca2+-ATPase inhibitors. Biochem. Biophys. Res. Commun. 196: 1183-1187
Hato T, Pampori N, Shattil SJ (1998) Complementary roles for receptor clustering and conformational change in the adhesive and signaling functions of integrin aIIbb3. J. Cell Biol. 141: 1685-1695
Haverstick DM, Gray LS (1992) Lymphocyte adhesion mediated by lymphocyte function-associated antigen 1. Long term augmentation by transient increases in intracellular cAMP. J. Immunol. 149: 389-396
Heys KR, Truscott RJ (2008) The stiffness of human cataract lenses is a function of both age and the type of cataract. Exp. Eye Res. 86: 701-703
Hong J, Kim J, Baek J, Cha M, Lee J., Park S (2007) Cell migration driven by a mechanical stiffness gradient. Proceedings of the 2nd IEEE International Conference 797-800
Howe AK, Aplin AE, Juliano RL (2002) Anchorage-dependent ERK signaling—mechanisms and consequences. Curr. Opin. Genet. Dev. 12: 30-35
Huang C, Jacobson K, Schaller MD (2004) MAP kinases and cell migration. J. Cell Sci. 117: 4619-4628
Huang S, Chen CS, Ingber DE (1998) Control of cyclin D1, p27Kip1, and cell cycle progression in human capillary endothelial cells by cell shape and cytoskeletal tension. Mol. Biol. Cell 9: 3179-3193
Humphries MJ, Symonds EJ, Mould AP (2003) Mapping functional residues onto integrin crystal structures. Curr. Opin. Struct. Biol. 13: 236-243
Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110: 673-687
Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, Nomura S, Fujimoto J, Okada M, Yamamoto T (1995) Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377: 539-544
Ilic D, Damsky CH, Yamamoto T (1997) Focal adhesion kinase: at the crossroads of signal transduction. J. Cell Sci. 110: 401-407
Ingber DE (2006) Mechanical control of tissue morphogenesis during embryological development. Int. J. Dev. Biol. 50: 255-266
Jalili N, Laxminarayana K (2004) A review of atomic force microscopy imaging systems: application to molecular metrology and biological sciences. Mechatronics 14: 907-945
Jiang G, Giannone G, Critchley DR, Fukumoto E, Sheetz MP (2003) Two-piconewton slip bond between fibronectin and the cytoskeleton depends on talin. Nature 424: 334-337
Jiang ST, Liao KK, Liao MC, Tang MJ (2000) Age effect of type I collagen on morphogenesis of Mardin-Darby canine kidney cells. Kidney Int. 57: 1539-1548
Jiang ST, Chiu SJ, Chen HC, Chuang WJ, Tang MJ (2001) Role of alpha(3)beta(1) integrin in tubulogenesis of Madin-Darby canine kidney cells. Kidney Int. 59: 1770-1778
Jockusch BM, Bubeck P, Giehl K, Kroemker M, Moschner J, Rothkegel M, Rudiger M, Schluter K, Stanke G, Winkler J (1995) The molecular architecture of focal adhesions. Annu. Rev. Cell Dev. Biol. 11: 379-416
Jongstra-Bilen J, Harrison R, Grinstein S (2003) Fcr-receptors induce Mac-1 (CD11b/CD18) mobilization and accumulation in the phagocytic cup for optimal phagocytosis. J. Biol. Chem. 278: 45720-45729
Juliano RL (2002) Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu. Rev. Pharmacol. Toxicol. 42: 283-323
Kallel F, Ophir J, Maguee K, Krouskop T (1998) Elastographic imagin of low-contrast elastic modulus distributions in tissue. Ultrasound in Mde. & Biol. 24: 409-425
Katsumi A, Milanini J, Kiosses WB, del Pozo MA, Kaunas R, Chien S, Haha KM, Schwartz MA (2002) Effects of cell tension on the small GTPase Rac. J. Cell Biol. 158: 153-164
Khoshnan A, Bae D, Tindell CA, Nel AE (2000) The physical association of protein kinase C针 with a lipid raft-associated inhibitor of kB factor kinase (IKK) complex plays a role in the activation of the NF-kB cascade by TCR and CD28. J. Immunol. 165: 6933-6940
Kifor O, Kifor I, Moore FD Jr., Butters RR Jr., Brown EM (2003) m-Calpain colocalizes with the calcium-sensing receptor (CaR) in caveolae in parathyroid cells and participates in degradation of the CaR. J. Biol. Chem. 278: 31167-31176
Kim M, Carman CV, Yang W, Salas A, Springer TA (2004) The primacy of affinity over clustering in regulation of adhesiveness of the integrin aLb2. J. Cell Biol. 167: 1241-1253
Kirber MT, Guerrero-Hernandez A, Bowman DS, Fogarty KE, Tuft RA, Singer JJ, Fay FS (2000) Multiple pathways responsible for the stretch-induced increase in Ca2+ concentration in toad stomach smooth muscle cells. J. Physiol. 524: 3-17
Kohler R, Schonfelder G, Hopp H, Distler A, Hoyer J (1998) Stretch-activated cation channel in human umbilical vein endothelium in normal pregnancy and in preeclampsia. J. Hypertens. 16: 1149-1156
Kucik DF, Dustin ML, Miller JM, Brown EJ (1996) Adhesion-activating phorbol ester increases the mobility of leukocyte integrin LFA-1 in cultured lymphocytes. J. Clin. Invest. 97: 2139-2144
Ku H, Meier KE (2000) Phosphorylation of paxillin via the ERK mitogen-activated protein kinase cascade in EL4 thymoma cells. J. Biol. Chem. 275: 11333-11340
Lafage-Proust MH, Thomas T, Guignandon A, Malaval L, Rattner A, Vico L (2007) Plasticity of osteoprogenitor cells. Joint Bone Spine 74: 536-539
Leach JB, Brown XQ, Jacot JG, DiMilla PA, Wong JY (2007) Neurite outgrowth and branching of PC12 cells on very soft substrates sharply decreases below a threshold of substrate rigidity. J. Neural Eng. 4: 26-34
Lee SE, Kam RD, Mofrad MR (2007) Force-induced activation of talin and its possible role in focal adhesion mechanotransduction. J. Biomech. 40: 2096-2106
Leitinger B, Hogg N (2002) The involvement of lipid rafts in the regulation of integrin function. J. Cell Sci. 115: 963-972
Leucht P, Kim JB, Currey JA, Brunski J, Helms JA (2007) FAK-mediated mechanotransduction in skeletal regeneration. PLoS ONE 2: e390
Levental I, Georges PC, Janmey PA (2007) Soft biological materials and their impact on cell function. Soft Matter. 3: 299-306
Li Z, Dranoff JA, Chan EP, Uemura M, Sevigny J, Wells RG (2007) Transforming growth factor-b and substrate stiffness regulate portal fibroblast activation in culture. Hepatology 46: 1246-1256
Liang CC, Chen HC (2001) Sustained activation of extracellular signal-regulated kinase stimulated by hepatocyte growth factor leads to integrin alpha 2 expression that is involved in cell scattering. J. Biol. Chem. 276: 21146-21152
Liao D, Arnett DK, Tyroler HA, Riley WA, Chambless LE, Szklo M, Heiss G (1999) Arterial stiffness and the development of hypertension: the ARIC study. Hypertension 34: 201-206
Liddington RC, Ginsberg MH (2002) Integrin activation takes shape. J. Cell Biol. 158: 833-839
Linder-Ganz E, Gefen A (2004) Mechanical compression-induced pressure sores in rat hindlimb: muscle stiffness, histology, and computational models. J. Appl. Physiol. 96: 2034-2049
Liu J, Liang M, Liu L, Malhotra D, Xie Z, Shapiro JI (2005) Ouabain-induced endocytosis of the plamalemmal Na/K-ATPase in LLC-PK1 cells requires caveolin-1. Kidney Int. 67: 1844-1854
Liu YH (2006) Renal fibrosis: New insights into the pathogenesis and therapeutics. Kidney Int. 69: 213-217
Lo CM, Wang HB, Dembe M, Wang YL (2000) Cell movement is guided by the rigidity of the substrate. Biophys. J. 79: 144-152
Luo BH, Strokovich K, Walz T, Springer TA, Takagi J (2004) Allosteric b1 integrin antibodies that stabilize the low affinity state by preventing the swing-out of the hybrid domain. J. Biol. Chem. 26: 27466-27471
Luque A, Gomez M, Puzon W, Takada Y, Sanchez-Madrid F, Cabanas C (1996) Activated conformations of very late activation integrins detected by a group of antibodies (HUTS) specific for a novel regulatory region (355-425) of the common b1 chain. J. Biol. Chem. 271: 11067-11075
Lyshchik A, Higashi T, Asato R, Tanaka S, Ito J, Hiraoka M, Insana FM, Brill AB, Saga T, Togashi K (2007) Cervical lymph node metastases: diagnosis at sonoelastography – initial experience. Radiology 243: 258-267
Matsubayashi Y, Ebisuya M, Honjoh S, Nishida E (2004) ERK activation propagates in epithelial cell sheets and regulates their migration during wound healing. Curr. Biol. 14: 731-735
McDaniel DP, Shaw GA, Elliott JT, Bhadriraju K, Meuse C, Chung KH, Plant AL (2007) The stiffness of collagen fibrils influences vascular smooth muscle cell phenotype. Biophys. J. 92: 1759-1769
Mijailovich SM, Stamenovic D, Brown R, Leith DE, Fredberg JJ (1994) Dynamic moduli of rabbit lung tissue and pigeon ligamentum propatagiale undergoing uniaxial cyclic loading. J. Appl. Physiol. 76: 773-782
Miller K, Chinzei K, Orssengo G, Bednarz P (2000) Mechanical properties of brain tissue in-vivo: experiment and computer simulation. J. Biomech. 33: 1369-1376
Morford LA, Forrest K, Logan B, Overstreet LK, Goebel J, Brooks WH, Roszman TL (2002) Calpain II colocalizes with detergent-insoluble rafts on human and Jurkat T-cells. Biochem. Biophys. Res. Commun. 295: 540-546
Munro S (2003) Lipid rafts: elusive or illusive? Cell 115: 377-388
Nanjundan M, Sun J, Zhao J, Zhou Q, Sims PJ, Wiedmer J (2003) Plasma membrane phospholipids scramblase 1 promotes EGF-dependent activation of c-Src through the epidermal growth factor receptor. J. Biol. Chem. 278: 37413-47418
Naruse K, Sokabe M (1993) Involvement of stretch-activated ion channels in Ca2+ mobilization to mechanical stretch in endothelial cells. Am. J. Physiol. 264: C1037-1044
Nasseri S, Bilston LE, Phan-Thien N (2002) Viscoelastic properties of pig kidney in shear, experimental results and modeling. Rheol. Acta. 41: 180-192
Nelson CM, Bissell MG (2006) Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 22: 287-309
Nguyen DH, Catling AD, Webb DJ, Sankovic M, Waker LA, Somlyo AV, Weber MJ, Gonias SL (1999) Myosin light chain kinase functions downstream of Ras/ERK to promote migration of urokinase-type plasminogen activator-stimulated cells in an integrin-selective manner. J. Cell Biol. 146: 149-164
Niv H, Gutman O, Kloog Y, Henis YI (2002) Activated K-Ras and H-Ras display different interactions with saturable nonraft sites at the surface of live cells. J. Cell Biol. 157: 865-872
Parsons JT, Martin KH, Slack JK, Taylor JM, Weed SA (2000) Focal adhesion kinase: a regulator of focal adhesion dynamics and cell movement. Oncogene 19: 5606-5613
Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, Reinhart-King CA, Margulies SS, Dembo M, Boettiger D, Hammer DA, Weaver VM (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8: 241-254
Ratnikov BL, Partridge AW, Ginsberg MH (2005) Integrin activation by talin. J. Thromb Haemost. 3: 1783-1790
Pelham RJ, Wang YL (1997) Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl. Acad. Sci. USA 94: 13661-13665
Pizzo P, Viola A (2003) Lymphocyte lipid rafts: structure and function. Curr. Opin. Immunol. 15: 255-260
Rodgers W, Farris D, Mishra S (2005) Merging complexes: properties of membrane raft assembly during lymphocyte signaling. Trends Immunol. 26: 97-103
Pommerenke H, Schreiber E, Durr F, Nebe B, Hahnel C, Moller W, Rychly J (1996) Stimulation of integrin receptors using a magnetic drag force device induces an intracellular free calcium response. Eur. J. Cell Biol. 70: 157-164
Rabinovich Y, Esayanur M, Daosukho S, Byer K, El-Shall H, Khan S (2005) Atomic force microscopy measurement of the elastic properties of the kidney epithelial cells. J. Colloid Interface Sci. 285: 125-135
Ratnikov BL, Partridge AW, Ginsberg MH (2005) Integrin activation by talin. J. Thromb Haemost. 3: 1783-1790
Rodgers W, Farris D, Mishra S (2005) Merging complexes: properties of membrane raft assembly during lymphocyte signaling. Trends Immunol. 26: 97-103
Rotsch C, Radmacher M (2000) Drug-induced changes of cytoskeletal structure and mechanics in fibroblasts: an atomic force microscopy study. Biophys. J. 78: 520-535
Rouviere O, Dresner MA, Rossman PJ, Burgart LJ, Fidler FL, Ehman RL (2006) MR elastography of the liver: preliminary results. Radiology 240: 440-448
Ruknudin A, SachsF, Bustamante JO (1993) Stretch-activated ion channels in tissue-cultured chick heart. Am. J. Physiol. 264: H960-972
Salaun C, James DJ, Chamberlain LH (2004) Lipid rafts and the regulation of exocytosis. Traffic 5: 255-264
Salazar EP, Rozengurt E (2001) Src family kinases are required for integrin-mediated but not for G protein-coupled receptor stimulation of focal adhesion kinase autophosphorylation at Tyr-397. J. Biol. Chem. 276: 17788-17795
Sawada Y, Nakamura K, Doi K, Takeda K, Tobiume K, Saitho M, Morita K, Komuro I, de Vos K, Sheetz M, Ichijo H (2001) Rap1 is involved in cell stretching modulation of p38 but not ERK or JNK MAP kinase. J. Cell Sci. 114: 1221-1227
Sawada Y, Tamada M, Dubin-Thaler BJ, Cherniavskaya O, Sakai R, Tanaka S, Sheetz MP (2006) Force sensing by mechanical extension of the Src family kinase substrate p130cas. Cell 127: 1015-1026
Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT (1994) Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol. Cell. Biol. 14: 1680-1688
Schlaepfer DD, Hunter T (1996) Evidence for in vivo phosphorylation of the Grb2 SH2-domain binding site on focal adhesion kinase by Src-family protein-tyrosine kinases. Mol. Cell. Biol. 16: 5623-5633
Schlaepfer DD, Hauck CR, Sieg DJ (1999) Signaling through focal adhesion kinase. Prog. Biophys. Mol. Biol. 7: 435-478
Schmidt C, Pommerenke H, Durr F, Nebe B, Rychly J (1998) Mechanical stressing of integrin receptors induces enhanced tyrosine phosphorylation of cytoskeletally anchored proteins. Cell 273: 5081-5085
Segarra M, Vilardell C, Matsumoto K, Esparza J, Lozano E, Serra-Pages C, Urbano-Marquez A, Yamada KM, Cid MC (2005) Dual function of focal adhesion kinase in regulating integrin-induced MMP-2 and MMP-9 release by human T lymphoid cells. FASEB. J. 19: 1875-1877
Shen J, Luscinskas FW, Connolly A, Dewey CF, Gimbrone MA (1992) Fluid shear stress modulates cytosolic free calcium in vascular endothelial cells. Am. J. Physiol. 262: C384-390
Shi Q, Boettinger D (2003) A novel mode for integrin-mediated signaing: tethering is required for phosphorylation of FAKY397. Mol. Biol. Cell 14: 4306-4315
Shimaoka M, Takagi J, Springer TA (2002) Conformational regulation of integrin structure and function. Annu. Rev. Biophys. Biomol. Struct. 31:485-516
Sieg DJ, Hauck CR, Schlaepfer DD (1999) Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J. Cell Sci. 112: 2677-2691
Sigurdson W, Ruknudin A, Sachs F (1992) Calcium imaging of mechanically induced fluxes in tissue-cultured chick heart: role of stretch-activated ion channels. Am. J. Physiol. 262: H1110-1115
Simons K, Toomre D (2000) Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1: 31-39
Smith JW, Piotrowicz RS, Mathis D (1994) A mechanism for divalent cation regulation of b3 integrins. J. Biol. Chem. 269: 960-967
Sowa G, Pypaert M, Sessa WC (2001) Distinction between signaling mechanisms in lipid rafts vs. caveolae. Proc. Natl. Acad. Sci. USA. 98: 14072-14077
Subauste MC, Pertz O, Adamson ED, Turner CE, Junger S, Hahn KM (2004) Vinculin modulation of paxillin-FAK interactions regulates ERK to control survival and motility. J. Cell Biol. 165: 371-381
Subramanian A, Lin HY (2005) Crosslinked chitosan: its physical properties and the effects of matrix stiffness on chondrocyte cell morphology and proliferation. J. Biomed. Mater. Res. A. 75: 742-753
Tabernero L, Aricescu AR, Jones EY, Szedlacsek SE (2008) Protein tyrosine phosphatases: structure-function relationships. FESEB J. 275: 867-882
Takagi J, Springer TA (2002) Integrin activation and structural rearrangement. Immunol. Rev. 186: 141-163
Taylor JM, Mack CP, Nolan K, Regan CP, Owens GK, Parsons JT (2001) Selective expression of an endogenous inhibitor of FAK regulates proliferation and migration of vascular smooth muscle cells. Mol. Cell Biol. 21: 1565-1572
Taylor LS, Rubens DJ, Porter BC, Wu Z, Baggs RB, di Sant’Agnese PA, Nadasdy G, Pasternack D, Messing EM, Nigwekar P, Parker KJ (2005) Prostate cancer: three-dimensional sonoelastography for in vitro detection. Radiology 237: 981-985
Tompa P, Emori Y, Sorimachi H, Suzuki K, Friedrich P (2001) Domain III of calpain is a ca2+-regulated phospholipids-binding domain. Biochem. Biophys. Res. Commun. 280: 1333-1339
Thomas A, Kummel S, Gemeinhardt O, Fischer T (2007) Real-time sonoelastography of the cervix: tissue elasticity of the normal and abnormal cervix. Acad. Radiol. 14: 193-200
Thomas TW, DiMilla PA (2000) Spreading and motility of human glioblastoma cells on sheets of silicone rubber depend on substratum compliance. Med. Biol. Eng. Comput. 38: 360-370
Van Kooyk Y, Figdor CG (2000) Avidity regulatio of integrins: the driving force in leukocyte adhesion. Curr. Opin. Cell Biol. 12: 542-547
Venkatachalam K, Montell C (2007) TRP channels. Annu. Rev. Biochem. 76: 387-417
Vogel V, Sheetz M (2006) Local force and geometry sensing regulate cell functions. Nat. Rev. Mol. Cell Biol. 7: 265-275
Volberg T, Romer L, Zamir E, Geiger B (2001) pp60c-src and related tyrosine kinases: a role in the assembly and reorganization of matrix adhesions. J. Cell Sci. 114: 2279-2289
von Wichert G, Haimovich B, Fen GS, Sheetz MP (2003) Force-dependent integrin-cytoskeleton linkage formation requires downregulation of focal complex dynamics by Shp2. EMBO J. 22: 5023-5035
von Wichert G, Jiang G, Kostic A, Vos KD, Sap J, Sheetz MP (2003) RPTP-a acts as a transducer of mechanical force on av/b3-integrin-cytoskeleton linkages. J. Cell Biol. 161: 143-153
von Wnuck Lipinski K, Keul P, Lucke S, Heusch G, Wohlschlaeger J, Baba HA, Levkau B (2006) Degraded collagen induces calpain-mediated apoptosis and destruction of the X-chromosome-linked inhibitor of apoptosis (xIAP) in human vascular sooth muscle cells. Cardiovasc. Res. 69: 697-705
Wang CZ, Hsu YM, Tang MJ (2005) Function of discoidin domain receptor I in HGF-induced branching tubulogenesis of MDCK cells in collagen gel. J. Cell Physiol. 203: 295-304
Wang CZ, Su HW, Hsu YC, Shen MR, Tang MJ (2006) A discoidin domain receptor 1/SHP-2 signaling complex inhibits a2b1-integrin-mediated signal transducers and activators of transcription 1/3 activation and cell migration. Mol. Biol. Cell 17: 2839-2852
Wang HB, Dembo M, Wang YL (2000) Substrate flexibility regulates growth and apoptosis of normal but not transformed cells. Am. J. Physiol. Cell Physiol. 279: C1345-C1350
Wang N, Butler JP, Ingber DE (1993) Mechanotransduction across the cell surface and through the cytoskeleton. Science 260: 1124-1127
Wang N, Ingber DE (1994) Control of cytoskeletal mechanics by extracellular matrix, cell shape, and mechanical tension. Biophys. J. 66: 2181-2189
Wang YH, Chiu WT, Wang YK, Wu CC, Chen TL, Teng CF, Chang WT, Chang HC, Tang MJ (2007) Deregulation of AP-1 protein family in collagen gel-induced epithelial cell apoptosis mediated by low substratum rigidity. J. Biol. Chem. 282: 752-763
Wang YL, Pelham RJ (1998) Preparation of a flexible, porous polyacrylamide substrate for mechanical studies of cultured cells. Methods Enzymol. 298: 489-496
Wang YK, Lin HH, Tang MJ (2001) Collagen gel overlay induces two phases of apoptosis in MDCK cells. Am. J. Physiol. Cell Physiol. 280: C1440-1448
Wang YK, Wang YH, Wang CZ, Sung JM, Chiu WT, Lin SH, Chang YH Tang MJ (2003) Rigidity of collagen fibrils control collagen gel–induced down-regulation of focal adhesion complex proteins mediated by a2b1 integrin. J. Biol. Chem. 278: 21886-21892
Weeber HA, Eckert G, Soergel F, Meyer CH, Pechhold W, van der Heijed RGL (2005) Dynamic mechanical properties of human lenses. Exp. Eye Res. 80: 425-434
Wegener KL, Partridge AW, Han J, Pickford AR, Liddington RC, Ginsberg MH, Campbell ID (2007) Structural basis of integrin activation by talin. Cell 128: 171-182
Weitzel WF, Kim K, Rubin JM, Xie H, O’Donnell M (2005) Renal advances in ultrasound elasticity imaging: measuring the compliance of arteries and kidneys in end-stage renal disease. Blood Purif. 23: 10-17
Weitzman JB, Pasqualini R, Takada Y, Hemler ME (1993) The function and distinctive regulation of the integrin VLA-3 in cell adhesion, spreading and homotypic cell aggregation. J. Biol. Chem. 268: 8651-8657
Wellman PS, Howe RD, Dewagan N, Cundari MA, Dalton E, Kern KA (1999) Harvard Biorobotics Laboratory Technical Report
Wells RG (2005) The role of matrix stiffness in hepatic stellate cell activation and liver fibrosis. J. Clin. Gastroenterol. 39: S158-S161
White MA, Anderson RG (2001) Which Ras rides the raft? Nat. Cell Biol. 3: E172
Wozniak MA, Desai R, Solski PA, Der CJ, Keely PJ (2003) ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix. J. Cell Biol. 163: 583-595
Wu Y, Cazorla O, Labeit D, Labeit S. Granzier H (2000) Changes in titin and collagen underlie diastolic stiffness diversity of cardiac muscle. J. Mol. Cell Cardiol. 32: 2151-2161
Wu CC, Ding SJ, Wang YH, Tang MJ, Chang HC (2005) Mechanical properties of collagen gels derived from rats of different ages. J. Biomater. Sci. Polymer Edn. 16: 1261-1275
Xing Z, Chen HC, Nowlen JK, Taylor SJ, Shalloway D, Guan JL (1994) Direct interaction of v-Src with the focal adhesion kinase mediated by the Src SH2 domain. Mol.Biol. Cell 5: 413-421
Xiong JP, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott DL, Andrzej J, Goodman SL, Arnaout MA (2001) Crystal structure of the extracellular segment of integrin avb3. Science 294: 339-345
Xiong JP, Stehle T, Zhang R, Joachimiak A, Frech M, Goodman SL, Arnaout MA (2002) Crystal structure of the extracellular segment of integrin 脉v刍3 in complex with an Arg-Gly-Asp ligand. Science 296: 151-155
Yamada KM, Miyamoto S (1995) Integrin transmembrane signaling and cytoskeletal control. Curr. Opin. Cell Biol. 7: 681-689
Yauch RL, Felsenfeld DP, Kraeft SK, Chen LB, Sheetz MP, Hemler ME (1997) Mutational evidence for control of cell adhesion through integrin diffusion/clustering, independent of ligand binding. J. Exp. Med. 186: 1347-1355
Yeh WC, Li PC, Jeng YM, Hsu HC, Kuo PL, Li ML, Yang PM, Lee PH (2002) Elastic modulus measurements of human liver and correlation with pathology. Ultrasound in Med. & Biol. 28: 467-474
Yeung T, Georges PC, Flanagan LA, Marg B, Ortiz M, Funaki M, Zahir N, Ming W, Weaver V, Janmey PA (2005) Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil. Cytoskeleton 60: 24-34
Young RM, Holowka D, Baird B (2003) A lipid raft environment enhances Lyn kinase activity by protecting the active site tyrosine from dephosphorylation. J. Biol. Chem. 278: 20746-20752
Yuan H, Kononov S, Canalcante FSA, Lutchen KR, Ingenito EP, Suki B (2000) Effects of collagenase and elastase on the mechanical properties of lung tissue strips. J. Appl. Physiol. 89: 3-14
Yuan HC, Ingenito EP, Suki B (1997) Dynamic properties of lung parenchyma: mechanical contributions of fiber network and interstitial cells. J. Appl. Physiol. 83: 1420-1431
Yuan HC, Kononov S, Cavalcante FSA, Lutchen KR, Ingenito EP, Suki B (2000) Effects of collagenase and elastase on the mechanical properties of lung tissue strips. J. Appl. Physiol. 89: 3-14
Zacharias DA, Violin JD, Newton AC, Tsien RY (2002) Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells. Science 296: 913-916
Zaman MH, Trapani LM, Sieminski A, MacKellar D, Gong H, Kamm RD, Wells A, Lauffenburger DA, Matsudaira P (2006) Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis. Proc. Natl. Acad. Sci. USA 103: 10889-10894
Zamir E, Geiger B (2001) Molecular complexity and dynamics of cell matrix adhesions. J. Cell Sci. 114: 3583-3590
Zeisberg M, Kalluri R (2004) The role of epithelial-to-mesenchymal transition in renal fibrosis. J. Mol. Med. 82: 175-181