Review Article | Published:

Focal adhesion kinase: in command and control of cell motility

Nature Reviews Molecular Cell Biology volume 6, pages 5668 (2005) | Download Citation

Subjects

Abstract

A central question in cell biology is how membrane-spanning receptors transmit extracellular signals inside cells to modulate cell adhesion and motility. Focal adhesion kinase (FAK) is a crucial signalling component that is activated by numerous stimuli and functions as a biosensor or integrator to control cell motility. Through multifaceted and diverse molecular connections, FAK can influence the cytoskeleton, structures of cell adhesion sites and membrane protrusions to regulate cell movement.

Key points

  • In 1992, focal adhesion kinase (FAK) was identified as a substrate for viral Src and as a highly tyrosine-phosphorylated protein that localized to cell adhesion sites known as focal contacts. Since then, FAK has been shown to have a key role in both normal and tumour cell migration downstream of growth factor- and integrin- receptors. It is the formation of a FAK–Src signalling complex that is an initial and important event required for maximal FAK activation and cell migration.

  • FAK can be activated through intermolecular and intramolecular mechanisms, and tyrosine-phosphorylated FAK promotes interactions with various Src-homology (SH)2- and SH3-containing proteins. These proteins allow FAK activation to be connected to several signalling pathways such as the extracellular signal-regulated kinase 2 (ERK2)/mitogen-activated protein kinase (MAPK) cascade and small GTPases such as Rac and Rho. Phosphorylation of the C-terminal domain of FAK might control its localization to focal contacts by altering the binding of paxillin.

  • FAK functions as a signalling-protein scaffold for the assembly and subsequent maturation of focal contacts. FAK–Src kinase activity contributes to these events by promoting signalling that leads to the phosphorylation of phosphatidylinositol lipids. FAK–Src also functions to promote the disassembly of focal contacts, in part by activating intracellular proteases such as calpain and extracellular matrix metalloproteinases. New findings also link FAK–Src signalling to the regulation of cadherin-mediated cell–cell contacts.

  • In cell protrusions of migrating cells, coordinated changes in actin and microtubule structures are regulated by FAK signalling to Rho-family GTPases. FAK binds to and can phosphorylate GTPase-activating proteins (GAPs) and guanine nucleotide-exchange factors (GEFs) for Rho, and neuronal Wiskott–Aldrich syndrome protein (N-WASP), and can exert control over actin crosslinking by phosphorylating α-actinin.

  • The receptor-proximal position of FAK facilitates its role as an integrator of biochemical signals and mechanical forces that are experienced by moving cells. It is in this unique signalling position that FAK can regulate cytoskeletal or cell adhesion site dynamics and thereby control cell motility.

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References

  1. 1.

    & The integrin–actin connection, an eternal love affair. EMBO J. 22, 2324–2333 (2003).

  2. 2.

    , & Integrin signaling to the actin cytoskeleton. Curr. Opin. Cell Biol. 15, 572–582 (2003).

  3. 3.

    et al. Cell migration: integrating signals from front to back. Science 302, 1704–1709 (2003).

  4. 4.

    Focal adhesion kinase: the first ten years. J. Cell Sci. 116, 1409–1416 (2003). Provides a good overview of the early studies on FAK.

  5. 5.

    et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377, 539–544 (1995). Shows that null mutation of FAK results in defects in embryonic morphogenesis, and that FAK-null cells show enhanced focal-contact formation and cell motility defects in culture.

  6. 6.

    et al. FAK–Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nature Cell Biol. 6, 154–161 (2004).

  7. 7.

    , , , & Localized stabilization of microtubules by integrin- and FAK-facilitated Rho signaling. Science 303, 836–839 (2004). Provides evidence that FAK promotes cell polarization through the stabilization of microtubules at leading edges of motile cells.

  8. 8.

    et al. Focal adhesion kinase suppresses Rho activity to promote focal adhesion turnover. J. Cell Sci. 113, 3673–3678 (2000).

  9. 9.

    et al. Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells. Oncogene 18, 5646–5653 (1999).

  10. 10.

    et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc. Natl Acad. Sci. USA 98, 13790–13795 (2001).

  11. 11.

    et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1, 133–143 (2002).

  12. 12.

    et al. Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes. Clin. Cancer Res. 6, 2417–2423 (2000).

  13. 13.

    et al. Focal adhesion kinase is required for blood vessel morphogenesis. Circ. Res. 92, 300–307 (2003).

  14. 14.

    et al. Focal adhesion kinase is expressed in the angiogenic blood vessels of malignant astrocytic tumors in vivo and promotes capillary tube formation of brain microvascular endothelial cells. Clin. Cancer Res. 9, 2157–2165 (2003).

  15. 15.

    , , & v-Src SH3-enhanced interaction with focal adhesion kinase at β1 integrin-containing invadopodia promotes cell invasion. J. Biol. Chem. 277, 12487–12490 (2002).

  16. 16.

    , , , & FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. EMBO J. 21, 6289–6302 (2002).

  17. 17.

    et al. Differential regulation of cell motility and invasion by FAK. J. Cell Biol. 160, 753–767 (2003). This reference, together with reference 69, shows that constitutively active Src can bypass the need for FAK in promoting the turnover of focal contacts.

  18. 18.

    , & Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochim. Biophys. Acta 1692, 77–102 (2004). Provides a solid review on the role of FAK during embryonic development.

  19. 19.

    et al. Roles played by a subset of integrin signaling molecules in cadherin-based cell–cell adhesion. J. Cell Biol. 166, 283–295 (2004).

  20. 20.

    , , & Integrins in mechanotransduction. J. Biol. Chem. 279, 12001–12004 (2004).

  21. 21.

    , , , & A novel role for FAK as a protease-targeting adaptor protein. Regulation by p42 ERK and Src. Curr. Biol. 13, 1442–1450 (2003).

  22. 22.

    et al. Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res. 61, 7079–7090 (2001).

  23. 23.

    et al. FAK integrates growth-factor and integrin signals to promote cell migration. Nature Cell Biol. 2, 249–256 (2000).

  24. 24.

    et al. Human cytomegalovirus chemokine receptor US28-induced smooth muscle cell migration is mediated by focal adhesion kinase and Src. J. Biol. Chem. 278, 50456–50465 (2003). Together with reference 23, this paper shows that the FAK FERM domain has important roles in promoting growth-factor-stimulated and G-protein-stimulated cell motility.

  25. 25.

    et al. Regulation of the PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domain. Nature Cell Biol. 3, 439–444 (2001).

  26. 26.

    et al. Ezrin interacts with focal adhesion kinase and induces its activation independently of cell–matrix adhesion. J. Biol. Chem. 276, 37686–37691 (2001).

  27. 27.

    et al. PIAS1-mediated sumoylation of focal adhesion kinase activates its autophosphorylation. J. Biol. Chem. 278, 47434–47440 (2003). Shows that sumoylation of FAK within the FERM domain is associated with catalytic activation and preferential nuclear localization.

  28. 28.

    & Nuclear import of N-terminal FAK by activation of the FcεRI receptor in RBL-2H3 cells. Biochem. Biophys. Res. Comm. 314, 39–45 (2004).

  29. 29.

    et al. FAK induces expression of Prx1 to promote tenascin-C-dependent fibroblast migration. J. Cell Biol. 161, 393–402 (2003).

  30. 30.

    et al. Identification of transcription factor KLF8 as a downstream target of focal adhesion kinase in its regulation of cyclin D1 and cell cycle progression. Mol. Cell 11, 1503–1515 (2003).

  31. 31.

    , , & Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility. Front. Biosci. 8, 982–996 (2003).

  32. 32.

    & Regulation of integrin-mediated cellular responses through assembly of a CAS/Crk scaffold. Biochim. Biophys. Acta. 1692, 63–76 (2004).

  33. 33.

    Biochemical signals and biological responses elicited by the focal adhesion kinase. Biochim. Biophys. Acta. 1540, 1–21 (2001).

  34. 34.

    et al. Direct interaction of focal adhesion kinase with p190RhoGEF. J. Biol. Chem. 278, 24865–24873 (2003). Together with reference 79, shows that FAK can directly activate Rho through binding and phosphorylation of a GEF, and that this activation regulates axonal branching.

  35. 35.

    et al. Alternative splicing controls the mechanisms of FAK autophosphorylation. Mol. Cell. Biol. 22, 7731–7743 (2002).

  36. 36.

    , & Negative regulation of FAK signaling by SOCS proteins. EMBO J. 22, 5036–5046 (2003). This paper established a link between FAK activation, phosphorylation of Tyr397 and subsequent degradation of FAK.

  37. 37.

    , , & RAFTK/Pyk2-mediated cellular signalling. Cell. Signal 12, 123–133 (2000).

  38. 38.

    et al. Targeting Pyk2 to β1-integrin-containing focal contacts rescues fibronectin-stimulated signaling and haptotactic motility defects of focal adhesion kinase-null cells. J. Cell Biol. 152, 97–110 (2001).

  39. 39.

    et al. Phosphorylation of focal adhesion kinase at tyrosine 861 is crucial for Ras transformation of fibroblasts. J. Biol. Chem. 279, 29060–29065 (2004).

  40. 40.

    , & Characterization of an activated mutant of focal adhesion kinase: 'SuperFAK'. Biochem. J. 365, 591–603 (2002).

  41. 41.

    et al. Structures of the cancer-related Aurora-A, FAK, and EphA2 protein kinases from nanovolume crystallography. Structure (Camb.) 10, 1659–1667 (2002).

  42. 42.

    et al. Regulation of focal adhesion kinase by a novel protein inhibitor FIP200. Mol. Biol. Cell 13, 3178–3191 (2002).

  43. 43.

    et al. Signaling between focal adhesion kinase and Trio. J. Biol. Chem. 278, 13265–13270 (2003).

  44. 44.

    , & Regulation of focal adhesion kinase by its amino-terminal domain through an autoinhibitory interaction. Mol. Cell. Biol. 23, 8030–8041 (2003).

  45. 45.

    et al. PTPα regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration. J. Cell Biol. 160, 137–146 (2003).

  46. 46.

    et al. Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. J. Cell Biol. 161, 933–944 (2003).

  47. 47.

    et al. Src kinase activation by direct interaction with the integrin β cytoplasmic domain. Proc. Natl Acad. Sci. USA 100, 13298–13302 (2003). Shows that selected β-integrin subunits can bind and activate Src in the absence of a contribution from FAK.

  48. 48.

    Paxillin and focal adhesion signalling. Nature Cell Biol. 2, 231–236 (2000).

  49. 49.

    & Purification of pseudopodia from polarized cells reveals redistribution and activation of Rac through assembly of a CAS/Crk scaffold. J. Cell Biol. 156, 725–736 (2002).

  50. 50.

    et al. CAS promotes invasiveness of Src-transformed cells. Oncogene 23, 7406–7415 (2004).

  51. 51.

    Paxillin: a focal adhesion-associated adaptor protein. Oncogene 20, 6459–6472 (2001).

  52. 52.

    et al. Vinculin modulation of paxillin–FAK interactions regulates ERK to control survival and motility. J. Cell Biol. 165, 371–381 (2004).

  53. 53.

    , & The focal adhesion targeting (FAT) region of focal adhesion kinase is a four-helix bundle that binds paxillin. Nature Struct. Biol. 9, 101–106 (2002).

  54. 54.

    , & Structural insight into the mechanisms of targeting and signaling of focal adhesion kinase. Mol. Cell. Biol. 22, 2751–2760 (2002).

  55. 55.

    et al. NMR solution structure of the focal adhesion targeting domain of focal adhesion kinase in complex with a paxillin LD peptide: evidence for a two-site binding model. J. Biol. Chem. 279, 8441–8451 (2004).

  56. 56.

    et al. Targeting membrane-localized focal adhesion kinase to focal adhesions: roles of tyrosine phosphorylation and SRC family kinases. J. Biol. Chem. 278, 29115–29120 (2003).

  57. 57.

    et al. The focal adhesion targeting domain of focal adhesion kinase contains a hinge region that modulates tyrosine 926 phosphorylation. Structure (Camb.) 12, 881–891 (2004). References 53, 54, 55 and 57 provide structural analyses of the FAK FAT domain and the paxillin LD peptide binding, and show that Tyr925 phosphorylation might require conformational alterations in the FAT domain.

  58. 58.

    , , & Serine phosphorylation of focal adhesion kinase in interphase and mitosis: a possible role in modulating binding to p130Cas. Mol. Biol. Cell 12, 1–12 (2001).

  59. 59.

    , , & PDGF and FGF induce focal adhesion kinase (FAK) phosphorylation at Ser-910: dissociation from Tyr-397 phosphorylation and requirement for ERK activation. J. Cell Physiol. 200, 213–222 (2004).

  60. 60.

    , , , & Hepatocyte growth factor induces ERK-dependent paxillin phosphorylation and regulates paxillin–focal adhesion kinase association. J. Biol. Chem. 277, 10452–10458 (2002).

  61. 61.

    , , & Phosphorylation-dependent paxillin–ERK association mediates hepatocyte growth factor-stimulated epithelial morphogenesis. Mol. Cell 12, 1275–1285 (2003).

  62. 62.

    , , , & Live-cell monitoring of tyrosine phosphorylation in focal adhesions following microtubule disruption. J. Cell Sci. 116, 975–986 (2003).

  63. 63.

    , , & Early molecular events in the assembly of matrix adhesions at the leading edge of migrating cells. J. Cell Sci. 116, 4605–4613 (2003).

  64. 64.

    , & Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J. Cell Sci. 112, 2677–2691 (1999).

  65. 65.

    , , , & Dissecting the link between stress fibres and focal adhesions by CALI with EGFP fusion proteins. Nature Cell Biol. 4, 286–293 (2002).

  66. 66.

    et al. The cytoskeletal/non-muscle isoform of α-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase. J. Biol. Chem. 276, 28676–28685 (2001).

  67. 67.

    , , , & Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion. J. Biol. Chem. 273, 21125–21131 (1998).

  68. 68.

    , , & Force-dependent integrin–cytoskeleton linkage formation requires downregulation of focal complex dynamics by Shp2. EMBO J. 22, 5023–5035 (2003). Together with reference 67, this study shows that null mutation of SHP2 results in FAK hyperactivation, elevated α-actinin phosphorylation, and the failure to promote the maturation of integrin–cytoskeletal linkages.

  69. 69.

    & v-Src rescues actin-based cytoskeletal architecture and cell motility and induces enhanced anchorage independence during oncogenic transformation of focal adhesion kinase-null fibroblasts. J. Biol. Chem. 278, 47946–47959 (2003).

  70. 70.

    & Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 92, 827–839 (2003).

  71. 71.

    , , & Regulation of focal complex composition and disassembly by the calcium-dependent protease calpain. J. Cell Sci. 115, 3415–3425 (2002).

  72. 72.

    et al. Reduced cell migration and disruption of the actin cytoskeleton in calpain-deficient embryonic fibroblasts. J. Biol. Chem. 276, 48382–48388 (2001).

  73. 73.

    et al. MEKK1 regulates calpain-dependent proteolysis of focal adhesion proteins for rear-end detachment of migrating fibroblasts. EMBO J. 22, 3346–3355 (2003).

  74. 74.

    , , , & Src-mediated phosphorylation of focal adhesion kinase couples actin and adhesion dynamics to survival signaling. Mol. Cell. Biol. 24, 8113–8133 (2004).

  75. 75.

    et al. Calcium rises locally trigger focal adhesion disassembly and enhance residency of focal adhesion kinase at focal adhesions. J. Biol. Chem. 279, 28715–28723 (2004).

  76. 76.

    , , , & Overexpression of FAK promotes Ras activity through the formation of a FAK/p120RasGAP complex in malignant astrocytoma cells. Oncogene 23, 3962–3971 (2004).

  77. 77.

    , , & Roles of Rho-associated kinase and myosin light chain kinase in morphological and migratory defects of focal adhesion kinase-null cells. J. Biol. Chem. 277, 33857–33863 (2002).

  78. 78.

    , & Integrin engagement suppresses RhoA activity via a c-Src-dependent mechanism. Curr. Biol. 10, 719–722 (2000).

  79. 79.

    et al. Control of axonal branching and synapse formation by focal adhesion kinase. Nature Neurosci. 7, 1059–1069 (2004).

  80. 80.

    , , , & Focal adhesion kinase regulation of N-WASP subcellular localization and function. J. Biol. Chem. 279, 9565–9576 (2004).

  81. 81.

    , , & mDia mediates Rho-regulated formation and orientation of stable microtubules. Nature Cell Biol. 3, 723–729 (2001).

  82. 82.

    , & Cortical control of microtubule stability and polarization. Curr. Opin. Cell Biol. 16, 106–112 (2004).

  83. 83.

    et al. Integrins regulate Rac targeting by internalization of membrane domains. Science 303, 839–842 (2004).

  84. 84.

    , , , & Adhesion to the extracellular matrix regulates the coupling of the small GTPase Rac to its effector PAK. EMBO J. 19, 2008–2014 (2000).

  85. 85.

    et al. PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J. Cell Biol. 162, 281–291 (2003).

  86. 86.

    et al. Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration. Cell 114, 469–482 (2003).

  87. 87.

    , , , & Pyk2 and FAK regulate neurite outgrowth induced by growth factors and integrins. Nature Cell Biol. 2, 574–581 (2000).

  88. 88.

    Integrin activation. J. Cell Sci. 117, 657–666 (2004).

  89. 89.

    et al. Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle. EMBO J. 23, 2942–2951 (2004).

  90. 90.

    et al. Recruitment and regulation of phosphatidylinositol phosphate kinase type 1γ by the FERM domain of talin. Nature 420, 85–89 (2002).

  91. 91.

    , , , & Type Iγ phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature 420, 89–93 (2002).

  92. 92.

    et al. Phosphatidylinositol phosphate kinase type 1γ and β1-integrin cytoplasmic domain bind to the same region in the talin FERM domain. J. Biol. Chem. 278, 31202–31209 (2003).

  93. 93.

    et al. Tyrosine phosphorylation of type Iγ phosphatidylinositol phosphate kinase by Src regulates an integrin–talin switch. J. Cell Biol. 163, 1339–1349 (2003). Together with references 91 and 92, this reference shows that FAK–Src phosphorylation events function to control the composition of membrane lipids and the dynamics of focal contacts.

  94. 94.

    & Cadherins as modulators of cellular phenotype. Ann. Rev. Cell Dev. Biol. 19, 207–235 (2003).

  95. 95.

    & Increased Src activity disrupts cadherin/catenin-mediated homotypic adhesion in human colon cancer and transformed rodent cells. Cancer Res. 62, 2669–2674 (2002).

  96. 96.

    et al. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nature Cell Biol. 4, 632–638 (2002).

  97. 97.

    , , , & Endothelial barrier strengthening by activation of focal adhesion kinase. J. Biol. Chem. 278, 13342–13349 (2003).

  98. 98.

    & Sensing the environment: a historical perspective on integrin signal transduction. Nature Cell Biol. 4, E83–E90 (2002).

  99. 99.

    et al. The role of the dynamics of focal adhesion kinase in the mechanotaxis of endothelial cells. Proc. Natl Acad. Sci. USA 99, 3546–3551 (2002).

  100. 100.

    , , & Focal adhesion kinase is involved in mechanosensing during fibroblast migration. Proc. Natl Acad. Sci. USA 98, 11295–11300 (2001). Shows that FAK functions as an important environmental biosensor in promoting directional motility signals in response to changes in substrate flexibility.

  101. 101.

    , , & Induced focal adhesion kinase (FAK) expression in FAK-null cells enhances cell spreading and migration requiring both auto- and activation loop phosphorylation sites and inhibits adhesion-dependent tyrosine phosphorylation of Pyk2. Mol. Cell. Biol. 19, 4806–4818 (1999).

  102. 102.

    , & Cell interactions with three-dimensional matrices. Curr. Opin. Cell Biol. 14, 633–639 (2002).

  103. 103.

    et al. FAK promotes organization of fibronectin matrix and fibrillar adhesions. J. Cell Sci. 117, 177–187 (2004).

  104. 104.

    et al. FAK deficiency in cells contributing to the basal lamina results in cortical abnormalities resembling congenital muscular dystrophies. Neuron 40, 501–514 (2003). References 103 and 104 show that FAK has crucial roles in promoting 3D-matrix assembly and/or remodelling during development and in cell culture model systems.

  105. 105.

    , , & Taking cell–matrix adhesions to the third dimension. Science 294, 1708–1712 (2001).

  106. 106.

    , , , & Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a β1 integrin viability signaling pathway. J. Biol. Chem. 279, 33024–33034 (2004).

  107. 107.

    , , , & 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 (2003).

  108. 108.

    et al. Plasma membrane-associated pY397FAK is a marker of cytotrophoblast invasion in vivo and in vitro. Am. J. Pathol. 159, 93–108 (2001).

  109. 109.

    , & Invadopodia: unique methods for measurement of extracellular matrix degradation in vitro. Methods Cell Biol. 63, 613–627 (2001).

  110. 110.

    , & The v-Src SH3 domain facilitates a cell adhesion-independent association with focal adhesion kinase. J. Biol. Chem. 276, 17653–17662 (2001).

  111. 111.

    , & The focal adhesion kinase amino-terminal domain localises to nuclei and intercellular junctions in HEK 293 and MDCK cells independently of tyrosine 397 and the carboxy-terminal domain. Biochem. Biophys. Res. Comm. 299, 62–73 (2002).

  112. 112.

    , , & Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. J. Biol. Chem. 271, 26329–26334 (1996).

  113. 113.

    & Talin forges the links between integrins and actin. Nature Cell Biol. 5, 694–697 (2003).

  114. 114.

    et al. Differential regulation of Pyk2 and focal adhesion kinase (FAK). J. Biol. Chem. 273, 2384–2389 (1998).

  115. 115.

    et al. Regulation of the formation of osteoclastic actin rings by proline-rich tyrosine kinase 2 interacting with gelsolin. J. Cell Biol. 160, 565–575 (2003).

  116. 116.

    et al. Pyk2 and Src-family protein-tyrosine kinases compensate for the loss of FAK in fibronectin-stimulated signaling events but Pyk2 does not fully function to enhance FAK cell migration. EMBO J. 17, 5933–5947 (1998).

  117. 117.

    , , , & Pyk2 autophosphorylation, but not kinase activity, is necessary for adhesion-induced association with c-Src, osteoclast spreading, and bone resorption. J. Biol. Chem. 278, 11502–11512 (2003).

  118. 118.

    et al. Identification of a novel family of targets of Pyk2 related to Drosophila retinal degeneration B (rdgB) protein. Mol. Cell. Biol. 19, 2278–2288 (1999).

  119. 119.

    , & Interleukin (IL)-7 induces rapid activation of Pyk2, which is bound to Janus kinase 1 and IL-7Rα. J. Biol. Chem. 275, 7060–7065 (2000).

  120. 120.

    et al. Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration. Proc. Natl Acad. Sci. USA 100, 10740–10745 (2003). Shows that null mutation of the FAK-related kinase PYK2 results in integrin and chemokine-stimulated motility defects of macrophages that are not functionally compensated by FAK expression.

  121. 121.

    et al. Inhibition of the calcium-dependent tyrosine kinase (CADTK) blocks monocyte spreading and motility. J. Biol. Chem. 276, 3536–3542 (2001).

  122. 122.

    , , & Absence of marginal zone B cells in Pyk2-deficient mice defines their role in the humoral response. Nature Immunol. 1, 31–36 (2000).

  123. 123.

    , , & Src family kinases are required for integrin but not PDGFR signal transduction. EMBO J. 18, 2459–2471 (1999).

  124. 124.

    et al. Cardiovascular anomaly, impaired actin bundling and resistance to Src- induced transformation in mice lacking p130Cas. Nature Genet. 19, 361–365 (1998).

  125. 125.

    et al. The adaptor protein paxillin is essential for normal development in the mouse and is a critical transducer of fibronectin signaling. Mol. Cell. Biol. 22, 901–915 (2002).

  126. 126.

    , & Vinculin knockout results in heart and brain defects during embryonic development. Development 125, 327–337 (1998).

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Acknowledgements

S. Mitra is supported by a fellowship from the California Tobacco-Related Disease Research Program and D. Schlaepfer is supported by grants from the National Cancer Institute. This is manuscript 16827-IMM from The Scripps Research Institute.

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  1. The Scripps Research Institute, Department of Immunology, IMM21 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

    • Satyajit K. Mitra
    • , Daniel A. Hanson
    •  & David D. Schlaepfer

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David D. Schlaepfer.

Glossary

INTEGRINS

A large family of heterodimeric transmembrane proteins that function as receptors for cell-adhesion molecules.

EXTRACELLULAR MATRIX

(ECM). The complex, multi-molecular material that surrounds cells. The ECM comprises a scaffold on which tissues are organized, it provides cellular microenvironments and it regulates various cellular functions.

RHO-FAMILY GTPases

A subfamily of small (21 kDa) GTP-binding proteins that are related to Ras and that regulate the cytoskeleton. The nucleotide-bound state is regulated by GTPase-activating proteins, which catalyse hydrolysis of the bound GTP, and guanine nucleotide-exchange factors, which catalyse GDP–GTP exchange.

STRESS FIBRES

Also termed 'actin-microfilament bundles', these are bundles of parallel filaments that contain F-actin and other contractile molecules, and often stretch between cell attachments as if under stress.

LAMELLIPODIA

Broad, flat protrusions at the leading edge of a moving cell that are enriched with a branched network of actin filaments.

HeLa CELLS

An established tissue-culture strain of human epidermoid carcinoma cells, containing 70–80 chromosomes per cell. These cells were originally derived from tissue taken from a patient named Henrietta Lacks in 1951.

ADAPTOR PROTEINS

Proteins that augment cellular responses by recruiting other proteins to a complex. They usually contain several protein–protein interaction domains.

G-PROTEIN-COUPLED RECEPTOR

A seven-helix membrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and GTP-hydrolysing G-proteins to stimulate or inhibit the activity of a downstream enzyme.

SRC-HOMOLOGY (SH)3-DOMAIN

A protein sequence of 50 amino acids that recognizes and binds sequences that are rich in proline.

GTPase-ACTIVATING PROTEIN

(GAP). A protein that stimulates the intrinsic ability of a GTPase to hydrolyse GTP to GDP. Therefore, GAPs negatively regulate GTPases by converting them from active (GTP-bound) to inactive (GDP-bound).

AUTOPHOSPHORYLATION

The transfer of a phosphate group by a protein kinase either to a residue in the same kinase molecule (cis) or to a residue in a different kinase molecule but of the same type (trans).

SH2 DOMAIN

A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

SRC-FAMILY KINASES

Kinases that belong to the Src family of tyrosine kinases, the largest of the non-receptor-tyrosine-kinase families.

MARGINAL ZONE

A region in the spleen in which white blood cell precursors such as B-cells, granulocytes, macrophages and plasma-cells reside or transit through during primary or secondary immune responses.

ACTIVATION LOOP

A conserved structural motif in kinase domains, which needs to be phosphorylated for full activation of the kinase.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

MEMBRANE RUFFLE

A process that is formed by the movement of lamellipodia that are in the dynamic process of folding back onto the cell body from which they previously extended.

LD MOTIF

A short sequence found within proteins that has the consensus sequence LDXLLXXL and functions as a protein-binding interface.

MATRIX METALLOPROTEINASES

Proteolytic enzymes that degrade the extracellular matrix and have important roles in tissue remodelling and tumour metastasis.

LEADING EDGE

The thin margin of a lamellipodium that spans the area of the cell from the plasma membrane to a depth of about 1 μm into the lamellipodium.

ARP2/3 COMPLEX

A complex that consists of two actin-related proteins ARP2 and ARP3, along with five smaller proteins. When activated, the ARP2/3 complex binds to the side of an existing actin filament and nucleates the assembly of a new actin filament. The resulting branch structure is Y-shaped.

GANGLIOSIDE

An anionic glycosphingolipid that carries, in addition to other sugar residues, one or more sialic acid residues.

LIPID RAFTS

Lateral aggregates of cholesterol and sphingomyelin that are thought to occur in the plasma membrane.

ADHERENS JUNCTION

A cell–cell adhesion complex that contains classical cadherins and catenins that are attached to cytoplasmic actin filaments.

TIGHT JUNCTION

A circumferential ring at the apex of epithelial cells that seals adjacent cells to one another. Tight junctions regulate solute and ion flux between adjacent epithelial cells.

DOMINANT NEGATIVE

A defective protein that retains interaction capabilities and so competes with normal proteins, thereby impairing protein function.

TANGENTIAL FLUID SHEAR STRESS

A planar force exerted by the friction of a flowing substance — for example, forces experienced by endothelial cells as blood flows through capillaries.

CYTOTROPHOBLAST

The inner trophoblastic layer of cells that give rise to the syncytiotrophoblast facing the maternal circulation and constitute a layer through which all substances must pass from the mother to the fetus.

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DOI

https://doi.org/10.1038/nrm1549

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