Cell adhesion to the extracellular matrix (ECM) is essential for cell migration, proliferation, and embryonic development. Cells can contact the ECM through a wide range of matrix contact structures such as focal adhesions, podosomes, and invadopodia. Although they are different in structural design and basic function, they share common remodeling proteins such as integrins, talin, paxillin, and the tyrosine kinases FAK, Pyk2, and Src. In this paper, we compare and contrast the basic organization and role of focal adhesions, podosomes, and invadopodia in different cells. In addition, we discuss the role of the tyrosine kinases, FAK, Pyk2, and Src, which are critical for the function of the different adhesion structures. Finally, we discuss the essential role of these tyrosine kinases from the perspective of human diseases. 1. Introduction The extracellular matrix (ECM) is an insoluble supra-structure comprised of a variety of matrix components including fibronectin, glycosaminoglycans, chrondronectin, osteonectin, collagens, laminin, proteoglycans, and growth factors [1–6]. The ECM provides the scaffold for cell attachment which is necessary for several diverse cellular activities, including cytoskeletal remodeling, polarization, differentiation, migration, and invasion [7–9]. Binding to the ECM is regulated by various signaling pathways that control the assembly and disassembly of three distinct, but functionally related actin and integrin-containing adhesion structures known as focal adhesions, podosomes, and invadopodia. In this review, we will discuss our current understanding of the similarities and differences between focal adhesions, podosomes, and invadopodia. We also will highlight several important tyrosine kinases and other signaling proteins that are known to control the formation and function of these adhesion structures, and we will discuss their role in pathophysiology. 2. Focal Adhesions Focal adhesion formation and turnover has been used as a model system for understanding the mechanisms of cellular adhesion. Although focal adhesions, podosomes, and invadopodia share common signaling proteins, they are distinct in cellular architecture and function (summarized in Table 1). Focal adhesions, also known as “focal contacts,” were identified over 30 years ago by electron microscopy and described as electron-dense plaques associated with actin filament bundles [10]. Focal adhesions can be considered to be large protein assembly complexes that spread mechanical forces from sites of cell adhesion to the cell body. In addition, focal adhesions
References
[1]
E. Hohenester and J. Engel, “Domain structure and organisation in extracellular matrix proteins,” Matrix Biology, vol. 21, no. 2, pp. 115–128, 2002.
[2]
R. O. Hynes, “The extracellular matrix: not just pretty fibrils,” Science, vol. 326, no. 5957, pp. 1216–1219, 2009.
[3]
P. D. Yurchenco and B. L. Patton, “Developmental and pathogenic mechanisms of basement membrane assembly,” Current Pharmaceutical Design, vol. 15, no. 12, pp. 1277–1294, 2009.
[4]
B. Geiger, A. Bershadsky, R. Pankov, and K. M. Yamada, “Transmembrane extracellular matrix-cytoskeleton crosstalk,” Nature Reviews Molecular Cell Biology, vol. 2, no. 11, pp. 793–805, 2001.
[5]
H. C. Slavkin, “Combinatorial process for extracellular matrix influences on gene expression: a hypothesis,” Journal of Craniofacial Genetics and Developmental Biology, vol. 2, no. 2, pp. 179–189, 1982.
[6]
K. T. Chan, C. L. Cortesio, and A. Huttenlocher, “Fak alters invadopodia and focal adhesion composition and dynamics to regulate breast cancer invasion,” The Journal of Cell Biology, vol. 185, no. 2, pp. 357–370, 2009.
[7]
E. D. Hay, “Extracellular matrix,” The Journal of Cell Biology, vol. 91, no. 3, part 2, pp. 205s–223s, 1981.
[8]
C. H. Damsky, “Extracellular matrix-integrin interactions in osteoblast function and tissue remodeling,” Bone, vol. 25, no. 1, pp. 95–96, 1999.
[9]
A. De Arcangelis and E. Georges-Labouesse, “Integrin and ECM functions: roles in vertebrate development,” Trends in Genetics, vol. 16, no. 9, pp. 389–395, 2000.
[10]
M. Abercrombie, J. E. M. Heaysman, and S. M. Pegrum, “The locomotion of fibroblasts in culture. IV. Electron microscopy of the leading lamella,” Experimental Cell Research, vol. 67, no. 2, pp. 359–367, 1971.
[11]
M. A. Wozniak, K. Modzelewska, L. Kwong, and P. J. Keely, “Focal adhesion regulation of cell behavior,” Biochimica et Biophysica Acta, vol. 1692, no. 2-3, pp. 103–119, 2004.
[12]
R. O. Hynes, “Integrins: versatility, modulation, and signaling in cell adhesion,” Cell, vol. 69, no. 1, pp. 11–25, 1992.
[13]
M. A. Schwartz, M. D. Schaller, and M. H. Ginsberg, “Integrins: emerging paradigms of signal transduction,” Annual Review of Cell and Developmental Biology, vol. 11, pp. 549–599, 1995.
[14]
L. H. Romer, K. G. Birukov, and J. G. N. Garcia, “Focal adhesions: paradigm for a signaling nexus,” Circulation Research, vol. 98, no. 5, pp. 606–616, 2006.
[15]
R. Zaidel-Bar, S. Itzkovitz, A. Ma'ayan, R. Iyengar, and B. Geiger, “Functional atlas of the integrin adhesome,” Nature Cell Biology, vol. 9, no. 8, pp. 858–867, 2007.
[16]
E. Zamir and B. Geiger, “Components of cell-matrix adhesions,” Journal of Cell Science, vol. 114, no. 20, pp. 3577–3579, 2001.
[17]
Q. S. Du, X. R. Ren, Y. Xie, Q. Wang, L. Mei, and W. C. Xiong, “Inhibition of PYK2-induced actin cytoskeleton reorganization, PYK2 autophosphorylation and focal adhesion targeting by FAK,” Journal of Cell Science, vol. 114, no. 16, pp. 2977–2987, 2001.
[18]
D. Ilic, Y. Furuta, S. Kanazawa et al., “Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice,” Nature, vol. 377, no. 6549, pp. 539–544, 1995.
[19]
H. B. Wang, M. Dembo, S. K. Hanks, and Y. L. Wang, “Focal adhesion kinase is involved in mechanosensing during fibroblast migration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 20, pp. 11295–11300, 2001.
[20]
D. M. Suter and P. Forscher, “Transmission of growth cone traction force through apCAM-cytoskeletal linkages is regulated by Src family tyrosine kinase activity,” The Journal of Cell Biology, vol. 155, no. 4, pp. 427–438, 2001.
[21]
M. C. Frame, V. J. Fincham, N. O. Carragher, and J. A. Wyke, “v-Src's hold over actin and cell adhesions,” Nature Reviews Molecular Cell Biology, vol. 3, no. 4, pp. 233–245, 2002.
[22]
E. Zamir and B. Geiger, “Molecular complexity and dynamics of cell-matrix adhesions,” Journal of Cell Science, vol. 114, no. 20, pp. 3583–3590, 2001.
[23]
C. Grashoff, I. Thievessen, K. Lorenz, S. Ussar, and R. F？ssler, “Integrin-linked kinase: integrin's mysterious partner,” Current Opinion in Cell Biology, vol. 16, no. 5, pp. 565–571, 2004.
[24]
A. Angers-Loustau, J. F. C？té, A. Charest et al., “Protein tyrosine phosphatase-PEST regulates focal adhesion disassembly, migration, and cytokinesis in fibroblasts,” The Journal of Cell Biology, vol. 144, no. 5, pp. 1019–1031, 1999.
[25]
A. Bourdeau, N. Dubé, and M. L. Tremblay, “Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP,” Current Opinion in Cell Biology, vol. 17, no. 2, pp. 203–209, 2005.
[26]
C. E. Turner, “Paxillin and focal adhesion signalling,” Nature Cell Biology, vol. 2, no. 12, pp. E231–E236, 2000.
[27]
H. Yano, H. Uchida, T. Iwasaki et al., “Paxillin α and Crk-associated substrate exert opposing effects on cell migration and contact inhibition of growth through tyrosine phosphorylation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 16, pp. 9076–9081, 2000.
[28]
K. A. DeMali, C. A. Barlow, and K. Burridge, “Recruitment of the Arp2/3 complex to vinculin: coupling membrane protrusion to matrix adhesion,” The Journal of Cell Biology, vol. 159, no. 5, pp. 881–891, 2002.
[29]
I. D. Campbell and M. H. Ginsberg, “The talin-tail interaction places integrin activation on FERM ground,” Trends in Biochemical Sciences, vol. 29, no. 8, pp. 429–435, 2004.
[30]
D. R. Critchley, “Genetic, biochemical and structural approaches to talin function,” Biochemical Society Transactions, vol. 33, no. 6, pp. 1308–1312, 2005.
[31]
S. H. Lo, “Tensin,” The International Journal of Biochemistry and Cell Biology, vol. 36, no. 1, pp. 31–34, 2004.
[32]
Y. Wang, H. Cao, J. Chen, and M. A. McNiven, “A direct interaction between the large GTPase dynamin-2 and FAK regulates focal adhesion dynamics in response to active Src,” Molecular Biology of the Cell, vol. 22, no. 9, pp. 1529–1538, 2011.
[33]
C. D. Nobes and A. Hall, “Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia,” Cell, vol. 81, no. 1, pp. 53–62, 1995.
[34]
K. Burridge and K. Wennerberg, “Rho and Rac take center stage,” Cell, vol. 116, no. 2, pp. 167–179, 2004.
[35]
L. A. Cary, D. C. Han, T. R. Polte, S. K. Hanks, and J. L. Guan, “Identification of p130(Cas) as a mediator of focal adhesion kinase-promoted cell migration,” The Journal of Cell Biology, vol. 140, no. 1, pp. 211–221, 1998.
[36]
B. Geiger, J. P. Spatz, and A. D. Bershadsky, “Environmental sensing through focal adhesions,” Nature Reviews Molecular Cell Biology, vol. 10, no. 1, pp. 21–33, 2009.
[37]
S. K. Mitra, D. A. Hanson, and D. D. Schlaepfer, “Focal adhesion kinase: in command and control of cell motility,” Nature Reviews Molecular Cell Biology, vol. 6, no. 1, pp. 56–68, 2005.
[38]
J. D. Hildebrand, M. D. Schaller, and J. T. Parsons, “Identification of sequences required for the efficient localization of the focal adhesion kinase, pp125(FAK), to cellular focal adhesions,” The Journal of Cell Biology, vol. 123, no. 4, pp. 993–1005, 1993.
[39]
J. W. Thomas, M. A. Cooley, J. M. Broome et al., “The role of focal adhesion kinase binding in the regulation of tyrosine phosphorylation of paxillin,” The Journal of Biological Chemistry, vol. 274, no. 51, pp. 36684–36692, 1999.
[40]
M. D. Schaller, C. A. Otey, J. D. Hildebrand, and J. T. Parsons, “Focal adhesion kinase and paxillin bind to peptides mimicking β integrin cytoplasmic domains,” The Journal of Cell Biology, vol. 130, no. 5, pp. 1181–1187, 1995.
[41]
I. Eke, Y. Deuse, S. Hehlgans et al., “β(1) Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy,” The Journal of Clinical Investigation, vol. 122, no. 4, pp. 1529–1540, 2012.
[42]
M. G. Yeo, M. A. Partridge, E. J. Ezratty, Q. Shen, G. G. Gundersen, and E. E. Marcantonio, “Src SH2 arginine 175 is required for cell motility: specific focal adhesion kinase targeting and focal adhesion assembly function,” Molecular and Cellular Biology, vol. 26, no. 12, pp. 4399–4409, 2006.
[43]
E. J. Ezratty, M. A. Partridge, and G. G. Gundersen, “Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase,” Nature Cell Biology, vol. 7, no. 6, pp. 581–590, 2005.
[44]
A. Bruzzaniti, L. Neff, A. Sanjay, W. C. Horne, P. De Camilli, and R. Baron, “Dynamin forms a Src kinase-sensitive complex with Cbl and regulates podosomes and osteoclast activity,” Molecular Biology of the Cell, vol. 16, no. 7, pp. 3301–3313, 2005.
[45]
A. Bruzzaniti, L. Neff, A. Sandoval, L. Du, W. C. Horne, and R. Baron, “Dynamin reduces Pyk2 Y402 phosphorylation and Src binding in osteoclasts,” Molecular and Cellular Biology, vol. 29, no. 13, pp. 3644–3656, 2009.
[46]
P. A. Amato, E. R. Unanue, and D. L. Taylor, “Distribution of actin in spreading macrophages: a comparative study on living and fixed cells,” The Journal of Cell Biology, vol. 96, no. 3, pp. 750–761, 1983.
[47]
P. C. Marchisio, D. Cirillo, L. Naldini, M. V. Primavera, A. Teti, and A. Zambonin-Zallone, “Cell-substratum interaction of cultured avian osteoclasts is mediated by specific adhesion structures,” The Journal of Cell Biology, vol. 99, no. 5, pp. 1696–1705, 1984.
[48]
J. Wang, Y. Taba, J. Pang, G. Yin, C. Yan, and B. C. Berk, “GIT1 mediates vegf-induced podosome formation in endothelial cells. Critical role for PLCγ,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 2, pp. 202–208, 2009.
[49]
S. Linder, K. Hufner, U. Wintergerst, and M. Aefelbacher, “Microtubule-dependent formation of podosomal adhesion structures in primary human macrophages,” Journal of Cell Science, vol. 113, no. 23, pp. 4165–4176, 2000.
[50]
O. Destaing, F. Saltel, J. C. Géminard, P. Jurdic, and F. Bard, “Podosomes display actin turnover and dynamic self-organization in osteoclasts expressing actin-green fluorescent protein,” Molecular Biology of the Cell, vol. 14, no. 2, pp. 407–416, 2003.
[51]
K. Mizutani, H. Miki, H. He, H. Maruta, and T. Takenawa, “Essential role of neural Wiskott-Aldrich syndrome protein in podosome formation and degradation of extracellular matrix in Src-transformed fibroblasts,” Cancer Research, vol. 62, no. 3, pp. 669–674, 2002.
[52]
H. M. Kocher, J. Sandle, T. A. Mirza, N. F. Li, and I. R. Hart, “Ezrin interacts with cortactin to form podosomal rosettes in pancreatic cancer cells,” Gut, vol. 58, no. 2, pp. 271–284, 2009.
[53]
W. T. Chen, “Proteolytic activity of specialized surface protrusions formed at rosette contact sites of transformed cells,” Journal of Experimental Zoology, vol. 251, no. 2, pp. 167–185, 1989.
[54]
G. Tarone, D. Cirillo, and F. G. Giancotti, “Rous-sarcoma virus-transformed fibroblasts adhere primarily at discrete protrusions of the ventral membrane called podosomes,” Experimental Cell Research, vol. 159, no. 1, pp. 141–157, 1985.
[55]
V. V. Artym, Y. Zhang, F. Seillier-Moiseiwitsch, K. M. Yamada, and S. C. Mueller, “Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function,” Cancer Research, vol. 66, no. 6, pp. 3034–3043, 2006.
[56]
E. S. Clark, A. S. Whigham, W. G. Yarbrough, and A. M. Weaver, “Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia,” Cancer Research, vol. 67, no. 9, pp. 4227–4235, 2007.
[57]
S. Linder and P. Kopp, “Podosomes at a glance,” Journal of Cell Science, vol. 118, no. 10, pp. 2079–2082, 2005.
[58]
M. Gimona, R. Buccione, S. A. Courtneidge, and S. Linder, “Assembly and biological role of podosomes and invadopodia,” Current Opinion in Cell Biology, vol. 20, no. 2, pp. 235–241, 2008.
[59]
D. A. Murphy and S. A. Courtneidge, “The “ins” and “outs” of podosomes and invadopodia: characteristics, formation and function,” Nature Reviews Molecular Cell Biology, vol. 12, no. 7, pp. 413–426, 2011.
[60]
M. R. Block, C. Badowski, A. Millon-Fremillon et al., “Podosome-type adhesions and focal adhesions, so alike yet so different,” European Journal of Cell Biology, vol. 87, no. 8-9, pp. 491–506, 2008.
[61]
P. Jurdic, F. Saltel, A. Chabadel, and O. Destaing, “Podosome and sealing zone: specificity of the osteoclast model,” European Journal of Cell Biology, vol. 85, no. 3-4, pp. 195–202, 2006.
[62]
R. Buccione, J. D. Orth, and M. A. McNiven, “Foot and mouth: podosomes, invadopodia and circular dorsal ruffles,” Nature Reviews Molecular Cell Biology, vol. 5, no. 8, pp. 647–657, 2004.
[63]
M. A. McNiven, M. Baldassarre, and R. Buccione, “The role of dynamin in the assembly and function of podosomes and invadopodia,” Frontiers in Bioscience, vol. 9, pp. 1944–1953, 2004.
[64]
H. Gil-Henn, O. Destaing, N. A. Sims et al., “Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2-/- mice,” The Journal of Cell Biology, vol. 178, no. 6, pp. 1053–1064, 2007.
[65]
Y. Furuta, D. Ilic, S. Kanazawa, N. Takeda, T. Yamamoto, and S. Aizawa, “Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK,” Oncogene, vol. 11, no. 10, pp. 1989–1995, 1995.
[66]
M. Pfaff and P. Jurdic, “Podosomes in osteoclast-like cells: structural analysis and cooperative roles of paxillin, proline-rich tyrosine kinase 2 (Pyk2) and integrin αVβ3,” Journal of Cell Science, vol. 114, no. 15, pp. 2775–2786, 2001.
[67]
V. Betapudi, “Myosin II motor proteins with different functions determine the fate of lamellipodia extension during cell spreading,” PLoS ONE, vol. 5, no. 1, Article ID e8560, 2010.
[68]
T. Sato, M. D. C. Ovejero, P. Hou et al., “Identification of the membrane-type matrix metalloproteinase MT1-MMP in osteoclasts,” Journal of Cell Science, vol. 110, no. 5, pp. 589–596, 1997.
[69]
S. Burns, A. J. Thrasher, M. P. Blundell, L. Machesky, and G. E. Jones, “Configuration of human dendritic cell cytoskeleton by Rho GTPases, the WAS protein, and differentiation,” Blood, vol. 98, no. 4, pp. 1142–1149, 2001.
[70]
C. Itzstein, F. P. Coxon, and M. J. Rogers, “The regulation of osteoclast function and bone resorption by small GTPases,” Small GTPases, vol. 2, no. 3, pp. 117–130, 2011.
[71]
S. F. G. van Helden and P. L. Hordijk, “Podosome regulation by Rho GTPases in myeloid cells,” European Journal of Cell Biology, vol. 90, no. 2-3, pp. 189–197, 2011.
[72]
S. Ory, H. Brazier, G. Pawlak, and A. Blangy, “Rho GTPases in osteoclasts: orchestrators of podosome arrangement,” European Journal of Cell Biology, vol. 87, no. 8-9, pp. 469–477, 2008.
[73]
G. Giannone, G. Jiang, D. H. Sutton, D. R. Critchley, and M. P. Sheetz, “Talin1 is critical for force-dependent reinforcement of initial integrin-cytoskeleton bonds but not tyrosine kinase activation,” The Journal of Cell Biology, vol. 163, no. 2, pp. 409–419, 2003.
[74]
V. V. Artym, K. M. Yamada, and S. C. Mueller, “ECM degradation assays for analyzing local cell invasion,” Methods in Molecular Biology, vol. 522, pp. 211–219, 2009.
[75]
J. M. Delaissé, M. T. Engsig, V. Everts et al., “Proteinases in bone resorption: obvious and less obvious roles,” Clinica Chimica Acta, vol. 291, no. 2, pp. 223–234, 2000.
[76]
S. Linder and M. Aepfelbacher, “Podosomes: adhesion hot-spots of invasive cells,” Trends in Cell Biology, vol. 13, no. 7, pp. 376–385, 2003.
[77]
S. Hu, E. Planus, D. Georgess et al., “Podosome rings generate forces that drive saltatory osteoclast migration,” Molecular Biology of the Cell, vol. 22, no. 17, pp. 3120–3126, 2011.
[78]
I. Dikic, G. Tokiwa, S. Lev, S. A. Courtneidge, and J. Schlessinger, “A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation,” Nature, vol. 383, no. 6600, pp. 547–550, 1996.
[79]
H. Avraham, S. Y. Park, K. Schinkmann, and S. Avraham, “RAFTK/Pyk2-mediated cellular signalling,” Cellular Signalling, vol. 12, no. 3, pp. 123–133, 2000.
[80]
D. Davidson and A. Veillette, “PTP-PEST, a scaffold protein tyrosine phosphatase, negatively regulates lymphocyte activation by targeting a unique set of substrates,” The EMBO Journal, vol. 20, no. 13, pp. 3414–3426, 2001.
[81]
Y. Shen, G. Schneider, J. F. Cloutier, A. Veillette, and M. D. Schaller, “Direct association of protein-tyrosine phosphatase PTP-PEST with paxillin,” The Journal of Biological Chemistry, vol. 273, no. 11, pp. 6474–6481, 1998.
[82]
C. E. Turner, “Paxillin interactions,” Journal of Cell Science, vol. 113, no. 23, pp. 4139–4140, 2000.
[83]
S. Avraham, R. London, Y. Fu et al., “Identification and characterization of a novel related adhesion focal tyrosine kinase (RAFTK) from megakaryocytes and brain,” The Journal of Biological Chemistry, vol. 270, no. 46, pp. 27742–27751, 1995.
[84]
L. Buckbinder, D. T. Crawford, H. Qi et al., “Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 25, pp. 10619–10624, 2007.
[85]
M. A. Kacena, P. P. Eleniste, Y. H. Cheng et al., “Megakaryocytes regulate expression of Pyk2 isoforms and caspase-mediated cleavage of actin in osteoblasts,” The Journal of Biological Chemistry, vol. 287, no. 21, pp. 17257–17268, 2012.
[86]
L. T. Duong, P. T. Lakkakorpi, I. Nakamura, M. Machwate, R. M. Nagy, and G. A. Rodan, “PYK2 in osteoclasts is an adhesion kinase, localized in the sealing zone, activated by ligation of α(v)β3 integrin, and phosphorylated by Src kinase,” Journal of Clinical Investigation, vol. 102, no. 5, pp. 881–892, 1998.
[87]
A. Sanjay, A. Houghton, L. Neff et al., “Cbl associates with Pyk2 and Src to regulate Src kinase activity, αvβ3 integrin-mediated signaling, cell adhesion, and osteoclast motility,” The Journal of Cell Biology, vol. 152, no. 1, pp. 181–195, 2001.
[88]
O. Destaing, A. Sanjay, C. Itzstein et al., “The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts,” Molecular Biology of the Cell, vol. 19, no. 1, pp. 394–404, 2008.
[89]
A. Gupta, B. S. Lee, M. A. Khadeer et al., “Leupaxin is a critical adaptor protein in the adhesion zone of the osteoclast,” Journal of Bone and Mineral Research, vol. 18, no. 4, pp. 669–685, 2003.
[90]
S. N. Sahu, M. A. Khadeer, B. W. Robertson, S. M. Nú？ez, G. Bai, and A. Gupta, “Association of leupaxin with Src in osteoclasts,” American Journal of Physiology, vol. 292, no. 1, pp. C581–C590, 2007.
[91]
S. N. Sahu, S. Nunez, G. Bai, and A. Gupta, “Interaction of Pyk2 and PTP-PEST with leupaxin in prostate cancer cells,” American Journal of Physiology, vol. 292, no. 6, pp. C2288–C2296, 2007.
[92]
G. C. Ochoa, V. I. Slepnev, L. Neff et al., “A functional link between dynamin and the actin cytoskeleton at podosomes,” The Journal of Cell Biology, vol. 150, no. 2, pp. 377–389, 2000.
[93]
S. Han, A. Mistry, J. S. Chang et al., “Structural characterization of proline-rich tyrosine kinase 2 (PYK2) reveals a unique (DFG-out) conformation and enables inhibitor design,” The Journal of Biological Chemistry, vol. 284, no. 19, pp. 13193–13201, 2009.
[94]
A. H. Chishti, A. C. Kim, S. M. Marfatia et al., “The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane,” Trends in Biochemical Sciences, vol. 23, no. 8, pp. 281–282, 1998.
[95]
K. Hamada, T. Shimizu, T. Matsui, S. Tsukita, S. Tsukita, and T. Hakoshima, “Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain,” The EMBO Journal, vol. 19, no. 17, pp. 4449–4462, 2000.
[96]
Y. R. Pan, C. L. Chen, and H. C. Chen, “FAK is required for the assembly of podosome rosettes,” The Journal of Cell Biology, vol. 195, no. 1, pp. 113–129, 2011.
[97]
I. Ayala, M. Baldassarre, G. Caldieri, and R. Buccione, “Invadopodia: a guided tour,” European Journal of Cell Biology, vol. 85, no. 3-4, pp. 159–164, 2006.
[98]
S. Linder, “The matrix corroded: podosomes and invadopodia in extracellular matrix degradation,” Trends in Cell Biology, vol. 17, no. 3, pp. 107–117, 2007.
[99]
S. Linder, “Invadosomes at a glance,” Journal of Cell Science, vol. 122, no. 17, pp. 3009–3013, 2009.
[100]
M. Vicente-Manzanares and A. R. Horwitz, “Cell migration: an overview,” Methods in Molecular Biology, vol. 769, pp. 1–24, 2011.
[101]
I. Ayala, M. Baldassarre, G. Giacchetti et al., “Multiple regulatory inputs converge on cortactin to control invadopodia biogenesis and extracellular matrix degradation,” Journal of Cell Science, vol. 121, no. 3, pp. 369–378, 2008.
[102]
S. Tehrani, N. Tomasevic, S. Weed, R. Sakowicz, and J. A. Cooper, “Src phosphorylation of cortactin enhances actin assembly,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 29, pp. 11933–11938, 2007.
[103]
M. Marzia, R. Chiusaroli, L. Neff et al., “Calpain is required for normal osteoclast function and is down-regulated by calcitonin,” The Journal of Biological Chemistry, vol. 281, no. 14, pp. 9745–9754, 2006.
[104]
S. S. Stylli, T. T. I. Stacey, A. M. Verhagen et al., “Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation,” Journal of Cell Science, vol. 122, no. 15, pp. 2727–2740, 2009.
[105]
C. C. Mader, M. Oser, M. A. O. Magalhaes et al., “An EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion,” Cancer Research, vol. 71, no. 5, pp. 1730–1741, 2011.
[106]
T. Uruno, J. Liu, P. Zhang et al., “Activation of Arp2/3 complex-mediated actin polymerization by cortactin,” Nature Cell Biology, vol. 3, no. 3, pp. 259–266, 2001.
[107]
M. Baldassarre, A. Pompeo, G. Beznoussenko et al., “Dynamin participates in focal extracellular matrix degradation by invasive cells,” Molecular Biology of the Cell, vol. 14, no. 3, pp. 1074–1084, 2003.
[108]
S. Linder, C. Wiesner, and M. Himmel, “Degrading devices: invadosomes in proteolytic cell invasion,” Annual Review of Cell and Developmental Biology, vol. 27, pp. 185–211, 2011.
[109]
F. Kimura, K. Iwaya, T. Kawaguchi et al., “Epidermal growth factor-dependent enhancement of invasiveness of squamous cell carcinoma of the breast,” Cancer Science, vol. 101, no. 5, pp. 1133–1140, 2010.
[110]
M. Schoumacher, R. D. Goldman, D. Louvard, and D. M. Vignjevic, “Actin, microtubules, and vimentin intermediate filaments cooperate for elongation of invadopodia,” The Journal of Cell Biology, vol. 189, no. 3, pp. 541–556, 2010.
[111]
C. S. Pichot, C. Arvanitis, S. M. Hartig et al., “Cdc42-interacting protein 4 promotes breast cancer cell invasion and formation of invadopodia through activation of N-WASp,” Cancer Research, vol. 70, no. 21, pp. 8347–8356, 2010.
[112]
R. Buccione, G. Caldieri, and I. Ayala, “Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix,” Cancer and Metastasis Reviews, vol. 28, no. 1-2, pp. 137–149, 2009.
[113]
C. Albiges-Rizo, O. Destaing, B. Fourcade, E. Planus, and M. R. Block, “Actin machinery and mechanosensitivity in invadopodia, podosomes and focal adhesions,” Journal of Cell Science, vol. 122, no. 17, pp. 3037–3049, 2009.
[114]
U. Philippar, E. T. Roussos, M. Oser et al., “A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis,” Developmental Cell, vol. 15, no. 6, pp. 813–828, 2008.
[115]
D. A. Schafer, “Regulating actin dynamics at membranes: a focus on dynamin,” Traffic, vol. 5, no. 7, pp. 463–469, 2004.
[116]
G. Eitzen, “Actin remodeling to facilitate membrane fusion,” Biochimica et Biophysica Acta, vol. 1641, no. 2-3, pp. 175–181, 2003.
[117]
M. Egeblad and Z. Werb, “New functions for the matrix metalloproteinases in cancer progression,” Nature Reviews Cancer, vol. 2, no. 3, pp. 161–174, 2002.
[118]
M. Seiki, “Membrane-type 1 matrix metalloproteinase: a key enzyme for tumor invasion,” Cancer Letters, vol. 194, no. 1, pp. 1–11, 2003.
[119]
F. Saltel, T. Daubon, A. Juin, I. E. Ganuza, V. Veillat, and E. Génot, “Invadosomes: intriguing structures with promise,” European Journal of Cell Biology, vol. 90, no. 2-3, pp. 100–107, 2011.
[120]
M. A. Eckert and J. Yang, “Targeting invadopodia to block breast cancer metastasis,” Oncotarget, vol. 2, no. 7, pp. 562–568, 2011.
[121]
C. Badowski, G. Pawlak, A. Grichine et al., “Paxillin phosphorylation controls invadopodia/podosomes spatiotemporal organization,” Molecular Biology of the Cell, vol. 19, no. 2, pp. 633–645, 2008.
[122]
C. L. Cortesio, K. T. Chan, B. J. Perrin et al., “Calpain 2 and PTP1B function in a novel pathway with Src to regulate invadopodia dynamics and breast cancer cell invasion,” The Journal of Cell Biology, vol. 180, no. 5, pp. 957–971, 2008.
[123]
L. C. Kelley, A. G. Ammer, K. E. Hayes et al., “Oncogenic Src requires a wild-type counterpart to regulate invadopodia maturation,” Journal of Cell Science, vol. 123, no. 22, pp. 3923–3932, 2010.
[124]
L. Li, M. Okura, and A. Imamoto, “Focal adhesions require catalytic activity of Src family kinases to mediate integrin-matrix adhesion,” Molecular and Cellular Biology, vol. 22, no. 4, pp. 1203–1217, 2002.
[125]
S. Granot-Attas, C. Luxenburg, E. Finkelshtein, and A. Elson, “Protein tyrosine phosphatase epsilon regulates integrin-mediated podosome stability in osteoclasts by activating Src,” Molecular Biology of the Cell, vol. 20, no. 20, pp. 4324–4334, 2009.
[126]
D. J. Webb, K. Donais, L. A. Whitmore et al., “FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly,” Nature Cell Biology, vol. 6, no. 2, pp. 154–161, 2004.
[127]
H. Sasaki, K. Nagura, M. Ishino, H. Tobioka, K. Kotani, and T. Sasaki, “Cloning and characterization of cell adhesion kinase β, a novel protein- tyrosine kinase of the focal adhesion kinase subfamily,” The Journal of Biological Chemistry, vol. 270, no. 36, pp. 21206–21219, 1995.
[128]
R. Baron, “Molecular mechanisms of bone resorption: therapeutic implications,” Revue du Rhumatisme (English Edition), vol. 63, no. 10, pp. 633–638, 1996.
[129]
T. Miyazaki, A. Sanjay, L. Neff, S. Tanaka, W. C. Horne, and R. Baron, “Src kinase activity is essential for osteoclast function,” The Journal of Biological Chemistry, vol. 279, no. 17, pp. 17660–17666, 2004.
[130]
J. W. Triplett and F. M. Pavalko, “Disruption of α-actinin-integrin interactions at focal adhesions renders osteoblasts susceptible to apoptosis,” American Journal of Physiology, vol. 291, no. 5, pp. C909–C921, 2006.
[131]
S. A. Courtneidge, “Cell migration and invasion in human disease: the Tks adaptor proteins,” Biochemical Society Transactions, vol. 40, no. 1, pp. 129–132, 2012.
[132]
B. Blouw, D. F. Seals, I. Pass, B. Diaz, and S. A. Courtneidge, “A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth in vivo,” European Journal of Cell Biology, vol. 87, no. 8-9, pp. 555–567, 2008.
[133]
I. Ayala, G. Giacchetti, G. Caldieri et al., “Faciogenital dysplasia protein Fgd1 regulates invadopodia biogenesis and extracellular matrix degradation and is up-regulated in prostate and breast cancer,” Cancer Research, vol. 69, no. 3, pp. 747–752, 2009.
[134]
G. W. McLean, N. O. Carragher, E. Avizienyte, J. Evans, V. G. Brunton, and M. C. Frame, “The role of focal-adhesion kinase in cancer—a new therapeutic opportunity,” Nature Reviews Cancer, vol. 5, no. 7, pp. 505–515, 2005.
[135]
V. G. Brunton and M. C. Frame, “Src and focal adhesion kinase as therapeutic targets in cancer,” Current Opinion in Pharmacology, vol. 8, no. 4, pp. 427–432, 2008.
[136]
H. Lahlou, V. Sanguin-Gendreau, D. Zuo et al., “Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 51, pp. 20302–20307, 2007.
[137]
M. Luo, H. Fan, T. Nagy et al., “Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells,” Cancer Research, vol. 69, no. 2, pp. 466–474, 2009.
[138]
B. Tavora, S. Batista, L. E. Reynolds et al., “Endothelial FAK is required for tumour angiogenesis,” EMBO Molecular Medicine, vol. 2, no. 12, pp. 516–528, 2010.
[139]
N. Koon, R. Schneider-Stock, M. Sarlomo-Rikala et al., “Molecular targets for tumour progression in gastrointestinal stromal tumours,” Gut, vol. 53, no. 2, pp. 235–240, 2004.
[140]
T. Miyazaki, H. Kato, M. Nakajima et al., “FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma,” British Journal of Cancer, vol. 89, no. 1, pp. 140–145, 2003.
[141]
C. R. Hauck, D. A. Hsia, X. S. Puente, D. A. Cheresh, and D. D. Schlaepfer, “FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth,” The EMBO Journal, vol. 21, no. 23, pp. 6289–6302, 2002.
[142]
C. R. Hauck, D. A. Hsia, D. Ilic, and D. D. Schlaepfer, “v-Src SH3-enhanced interaction with focal adhesion kinase at β1 integrin-containing invadopodia promotes cell invasion,” The Journal of Biological Chemistry, vol. 277, no. 15, pp. 12487–12490, 2002.
[143]
C. Annerén, C. A. Cowan, and D. A. Melton, “The Src family of tyrosine kinases is important for embryonic stem cell self-renewal,” The Journal of Biological Chemistry, vol. 279, no. 30, pp. 31590–31598, 2004.
[144]
S. J. Parsons and J. T. Parsons, “Src family kinases, key regulators of signal transduction,” Oncogene, vol. 23, no. 48, pp. 7906–7909, 2004.
[145]
J. M. Su, L. Gui, Y. P. Zhou, and X. L. Zha, “Expression of focal adhesion kinase and α5 and β1 integrins in carcinomas and its clinical significance,” World Journal of Gastroenterology, vol. 8, no. 4, pp. 613–618, 2002.
[146]
I. Tanjoni, C. Walsh, S. Uryu et al., “PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments,” Cancer Biology and Therapy, vol. 9, no. 10, pp. 764–777, 2010.
[147]
S. Roelle, R. Grosse, T. Buech, V. Chubanov, and T. Gudermann, “Essential role of Pyk2 and Src kinase activation in neuropeptide-induced proliferation of small cell lung cancer cells,” Oncogene, vol. 27, no. 12, pp. 1737–1748, 2008.
[148]
S. Zhang, X. Qiu, Y. Gu, and E. Wang, “Up-regulation of proline-rich tyrosine kinase 2 in non-small cell lung cancer,” Lung Cancer, vol. 62, no. 3, pp. 295–301, 2008.
[149]
M. J. van Nimwegen, S. Verkoeijen, L. van Buren, D. Burg, and B. van de Water, “Requirement for focal adhesion kinase in the early phase of mammary adenocarcinoma lung metastasis formation,” Cancer Research, vol. 65, no. 11, pp. 4698–4706, 2005.
[150]
L. Tremblay, W. Hauck, A. G. Aprikian, L. R. Begin, A. Chapdelaine, and S. Chevalier, “Focal adhesion kinase (pp125FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma,” International Journal of Cancer, vol. 68, no. 2, pp. 164–171, 1996.
[151]
H. Sun, S. Pisle, E. R. Gardner, and W. D. Figg, “Bioluminescent imaging study: FAK inhibitor, PF-562,271, preclinical study in PC3M-luc-C6 local implant and metastasis xenograft models,” Cancer Biology and Therapy, vol. 10, no. 1, pp. 38–43, 2010.
[152]
P. P. Eleniste, L. Du, M. Shivanna, and A. Bruzzaniti, “Dynamin and PTP-PEST cooperatively regulate Pyk2 dephosphorylation in osteoclasts,” The International Journal of Biochemistry & Cell Biology, vol. 44, no. 5, pp. 790–800, 2012.
[153]
B. Desai, T. Ma, and M. A. Chellaiah, “Invadopodia and matrix degradation, a new property of prostate cancer cells during migration and invasion,” The Journal of Biological Chemistry, vol. 283, no. 20, pp. 13856–13866, 2008.
[154]
A. Gutenberg, W. Brück, M. Buchfelder, and H. C. Ludwig, “Expression of tyrosine kinases FAK and Pyk2 in 331 human astrocytomas,” Acta Neuropathologica, vol. 108, no. 3, pp. 224–230, 2004.
[155]
Z. Li, X. Yuan, Z. Wu, Z. Guo, P. Jiang, and Z. Wen, “Expressions of FAK and Pyk2 in human astrocytic tumors and their relationship with angiogenesis,” Chinese-German Journal of Clinical Oncology, vol. 7, no. 11, pp. 658–660, 2008.
[156]
T. P. Hecker, J. R. Grammer, G. Y. Gillespie, J. Stewart Jr., and C. L. Gladson, “Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples,” Cancer Research, vol. 62, no. 9, pp. 2699–2707, 2002.
[157]
Q. Shi, A. B. Hjelmeland, S. T. Keir et al., “A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth,” Molecular Carcinogenesis, vol. 46, no. 6, pp. 488–496, 2007.
[158]
A. H. Sikkema, S. H. Diks, W. F. A. den Dunnen et al., “Kinome profiling in pediatric brain tumors as a new approach for target discovery,” Cancer Research, vol. 69, no. 14, pp. 5987–5995, 2009.
[159]
S. M. Weis, S. T. Lim, K. M. Lutu-Fuga et al., “Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK,” The Journal of Cell Biology, vol. 181, no. 1, pp. 43–50, 2008.
[160]
Y. Duan, J. Learoyd, A. Y. Meliton, B. S. Clay, A. R. Leff, and X. Zhu, “Inhibition of Pyk2 blocks airway inflammation and hyperresponsiveness in a mouse model of asthma,” American Journal of Respiratory Cell and Molecular Biology, vol. 42, no. 4, pp. 491–497, 2010.
[161]
Y. Yu, S. A. Ross, A. E. Halseth et al., “Role of PYK2 in the development of obesity and insulin resistance,” Biochemical and Biophysical Research Communications, vol. 334, no. 4, pp. 1085–1091, 2005.
[162]
M. Okigaki, C. Davis, M. Falascat et al., “Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 19, pp. 10740–10745, 2003.
[163]
D. Lang, A. V. Glukhov, T. Efimova, and I. R. Efimov, “Role of Pyk2 in cardiac arrhythmogenesis,” American Journal of Physiology Heart and Circulatory Physiology, vol. 301, no. 3, pp. H975–H983, 2011.
[164]
G. M. Fabrizi, M. Ferrarini, T. Cavallaro et al., “Two novel mutations in dynamin-2 cause axonal Charcot-Marie-Tooth disease,” Neurology, vol. 69, no. 3, pp. 291–295, 2007.
[165]
J. B？hm, V. Biancalana, E. T. Dechene et al., “Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy,” Human Mutation, vol. 33, no. 6, pp. 949–959, 2012.
[166]
P. N. M. Sidiropoulos, M. Miehe, T. Bock et al., “Dynamin 2 mutations in Charcot-Marie-Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination,” Brain, vol. 135, no. 5, pp. 1395–1411, 2012.
