Manipulation of Focal Adhesion Signaling by Pathogenic Microbes
Abstract
:1. Introduction
2. Multiple Regulatory Mechanisms Control Focal Adhesion Dynamics
2.1. ECM Stiffness Sensing of FA Proteins
2.2. Tension Responsiveness of FA Proteins
2.3. Calpain and Caspase-Mediated Cleavage of FA Proteins
2.4. Autoinhibitory Mechanisms of FA Proteins
2.5. Nuclear Translocation of FA Proteins
2.6. Phosphorylation Events on Tyrosine and Serine/Threonine Residues of FA Proteins
3. Pathogenic Microbes Utilize “Outside–In” and “Inside–Out” Signaling during Host Remodeling
3.1. “Outside–In Signaling” upon Microbial Engagement with ECM or Integrin Receptors
3.1.1. TSA56
3.1.2. Opc
3.2. “Inside–Out Signaling” in Which Secreted Microbial Factors Signal from within the Cell
3.2.1. YopH
3.2.2. Certhrax
3.2.3. OspE
3.3. Effectors of Attaching and Effacing E. coli
3.3.1. EspO1
3.3.2. EspM
3.3.3. EspG
3.4. Vinculin-Mimetic Effectors
3.4.1. IpaA
3.4.2. Sca4
3.4.3. TarP
3.5. Manipulation of FA by Viral Proteins
3.5.1. KSHV TK
3.5.2. Tat
3.5.3. E7
4. Conclusions and Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
FA | Focal adhesion |
ECM | Extracellular matrix |
LD motif | Leucine–aspartic acid motif |
VBD | Vinculin-binding domain |
FAK | Focal adhesion kinase |
ILK | Integrin-linked kinase |
p130Cas | Crk-associated substrate |
RIAM | Rap1-interacting adaptor molecule |
FRET | Förster (Fluorescence) Resonance Energy Transfer |
ABS | Actin-binding site |
ROS | Reactive oxygen species |
EPEC | Enteropathogenic Escherichia coli |
EHEC | Enterohemorrhagic Escherichia coli |
E4orf4 | E4 open reading frame 4 |
CaM-LD | Calmodulin-like domain |
iPalm | Interferometric photoactivation and localization microscopy |
NES | Nuclear export sequence |
NIS | Nuclear import sequence |
PABP1 | Poly(A)-binding protein 1 |
AR | Androgen receptor |
ePABP | Polyadenylation binding protein |
GR | Glucocorticoid receptor |
NMP4 | Nuclear matrix protein 4 |
HPV | Human papillomavirus |
KSHV | Kaposi sarcoma herpesvirus |
AGS | Adenocarcinoma gastric epithelial cells |
RGD | Arg-Gly-Asp |
PAI | Pathogenicity island |
Vh | Vinculin head domain |
Vt | Vinculin tail domain |
EGFR | Epidermal growth factor receptor |
ROCK | Rho-associated protein kinase |
MLC | Myosin light chain |
MEF | Mouse embryonic fibroblasts |
HBMEC | Human brain microvascular endothelial cell |
TK | Thymidine kinase |
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FA Protein Phosphorylation Events with an Assigned Biological Function | |
---|---|
Phosphorylation Site | Function |
Paxillin—As summarized in [46] | |
Tyr 31; Tyr 118; Ser 178 | Regulation of Cell Migration and FA Turnover [165,166,167,168] |
Ser 106; Ser 231; Ser 290 | Regulation of Pax disassembly from FAs [169,170] |
Ser 126; Ser 130 | Translocation of Pax from FAs to the cytosol [171] |
Ser 398; Ser 403; Ser 457; Ser 481 | Adhesion regulation; Pax localization at FAs [172,173] |
Ser 272 | Regulation of Ras activity; adhesion/protrusion; inhibition of nuclear export [142] |
Ser 188; Ser 190 | Integrin Activation [174] |
Talin—As mapped in [175] | |
Thr 114; Thr 150 | Negative regulation of integrin activation; Regulation of calpain-mediated cleavage of talin and FA turnover [176,177,178] |
Thr 152 | Talin recruitment to integrin adhesion sites and maintaining muscle attachment in Drosophila [179] |
Ser 425 | Inhibits binding to Smurf1—thereby preventing talin head ubiquitylation and degradation; Favors adhesion assembly, talin activity and integrin activation [98] |
Ser 446 | Regulation of calpain-mediated cleavage of talin and FA turnover [178] |
Vinculin | |
Tyr 100; Tyr 1065 | Favors activation by promoting talin and actin binding; Regulates binding to the Arp2/3 complex; Focal adhesion development and maturation [180,181,182] |
Ser 1033; Ser 1045 | Favors activation by promoting talin and actin binding; Focal adhesion development and maturation [181] |
p130Cas | |
Tyr 249; Tyr 410 | Binding sites for Crk SH2 domain [183] |
Ser 139; Ser 437; Ser 639 | Intracellular localization [184] |
Focal Adhesion Kinase (FAK) | |
Tyr 397 | Major site of FAK autophosphorylation; Binding site for the SH2 domain of Src [185] |
Tyr 861 | Major site of phosphorylation by Src [186] |
Tyr 576; Tyr 577 | Promotes open FAK conformation; Facilitates scaffold and kinase functions [124] |
Tyr 925 | Promotes Grb2 SH2-mediated binding [187] |
Tyr 194 | Activation through relief of autoinhibition [188] |
Src—As summarized in [189] | |
Tyr 213 | Activation [190] |
Tyr 527 | Autoinhibitory phosphorylation site—promotes an inactive conformation [191] |
Tyr 416 | Activation from autophosphorylation [192] |
Ser 17 | Facilitates activation of the small G protein Rap1 [126] |
Thr 34; Thr 46; Ser 72 | Activation of pTyrosine527 Src [193] |
α-actinin-4 | |
Tyr 4; Tyr 31 | Reduces actin binding behavior [194] |
Tyr 265 | Enhanced actin binding behavior; Susceptibility to calpain-mediated cleavage [195] |
Zyxin | |
Ser 142 | Regulates release from autoinhibitory head: tail interaction; cell-cell adhesion regulation [127] |
RIAM | |
Tyr 340 | Translocation to plasma membrane; β2 integrin designated lymphocyte functional antigen 1 (LFA-1) activation [196] |
Tyr 45 | Release of autoinhibitory configuration [123] |
Microbial Adhesins That Modulate “Outside-In” Signaling | ||||
---|---|---|---|---|
Fibronectin | ||||
Adhesin/Microbe | Interactions Detected | Effect on Focal Signaling/Complex/Adhesion | Microbial Advantage | References |
FlpA/Campylobacter jejuni | Fibronectin: FlpA | Required for ERK 1/2 phosphorylation | Invasion | [204,205] |
CadF/Campylobacter jejuni | Fibronectin: CadF | Increased paxillin phosphorylation and actin polymerization | Invasion | [204,206] |
Opc/Neisseria meningitidis | OpC: serum factors | Increased phosporylation of Src and FA-associated proteins | Invasion | [207] |
SfbI/Streptococcus pyrogenes | Fibronectin: SfbI | Induces integrin clustering which results in the recruitment of paxillin, FAK, and other FA proteins to site of entry; intiates FAK autophosphorylation | Invasion | [208,209] |
FnBPA-B/Staphylococcus aureus | Fibronectin: FnBPA-B | Activation of integrin signalling, including FAK-Src mediated phosphorylation of cortactin which resulted in actin rearrangement and induced uptake | Invasion | [210,211] |
YadA/Enteropathogenic Yersinia | Fibronectin: YadA | Triggers FAK-Src complex formation and subsequent Ras activation | Invasion | [212,213] |
Beta-integrins | ||||
NadA/Neisseria meningitidis | NadA: α5β1 integrin | Uncharacterized | Invasion | [214] |
Invasin/Enteropathogenic Yersinia | Invasin: β1 integrins | FAK recruitment of a Src family kinase and phosphorylation of paxillin | Invasion | [215,216] |
CagL/Helicobacter pylori | CagL: α5β1/αVβ6 | Activates FAK and Src and triggers focal adhesion formation | Invasion | [217,218,219] |
TSA56/Orientia tsutsugamushi | TSA56: α5β1 integrin | Fibronectin-binding domain of TSA56 blocked bacterial internalization | Invasion | [220] |
Tat/HIV-1 | α5β3-integrin | Increased FAK phosphorylation, RhoA and Src activation | Spread | [221] |
Secreted Effectors that modulate “inside-out” signaling | ||||
p130Cas | ||||
Effector/Microbe | Interactions detected | Effect on focal signaling/complex/adhesion | Microbial Advantage | References |
YopH/Y. pseudotuberculosis | YopH: p130Cas | Cas disassembles focal complexes in presence of YopH | Cell detachment/spread | [222] |
YopH PTPase activity | Dephosphorylation of p130Cas, paxillin and FAK | Cell detachment/spread | [223,224] | |
Relocalization of FAK and Cas to the cytosol | Cell detachment/spread | [223] | ||
Dephosphorylation of of FYB, SKAP-HOM, p55 | Cell detachment/spread | [225,226] | ||
YopH(C403A) | Fyn and p130Cas localize to FAs in presence of kinase-dead YopH | Cell detachment/spread | [225] | |
YopH(Q11) | Does not bind p130Cas and is readily phagocytized | Colonization | [227] | |
YopH (N-term deleted) | Decreased substrate binding and decreased virulence in IP mouse model | Colonization | [224,227] | |
Paxillin | ||||
BE6/Bovine Papilloma Virus-1 | BE6: Paxillin | Depolymerizes actin stress fibers | Cell transformation | [160] |
BE6: Paxillin (LD1) | Blocks paxillin interaction with vinculin and FAK | Cell transformation | [162] | |
E6/HPV-16 | E6: Paxillin | LD1 domain of E6 interacts with Paxillin and decreases FA formation | Cell transformation | [161,162] |
EspC/Enteropathogenic E. coli | EspC: Paxillin | Serine protease activity of EspC cleaves Paxillin | Cell detachment/spread | [107] |
Vinculin | ||||
IpaA/Shigella dysentirae | IpaA (N-term): Vinculin | Blocks vinculin: talin interaction, vinculin binds F-actin and induces depolymerization of stress fibers | Invasion | [228] |
IpaA/Shigella flexneri | IpaA: Vinculin | Focal complexes form at invasion site | Invasion | [229] |
IpaA (VBS1–2): Vinculin | Recruitment of Vinculin to invasion site forms actin-vinculin cup around Shigellae | Invasion | [230] | |
IpaA (VBS3): Vinculin | Inhibition of head and tail domains and blocks vinculin-actin association | Invasion | [231] | |
IpaA: Vinculin | Vinculin-binding excludes Talin, preventing Talin: B1-integrin interaction | Cell rounding | [232] | |
TarP/Chlamydia caviae | TarP (VBD1–3): Vinculin | TarP binds vinculin, inducing actin polymerization at the invasion site | Invasion | [233] |
TarP/Chlamydia trachomatis | TarP (LDVBD): Vinculin | TarP C-term recruitment to FAs requires vinculin, and increases FA size and stability. | Adhesion | [234] |
Sca4/Rickettsia rickettsii | Sca4: Vinculin | Two VBD sites in Sca4 enable it to outcompetes alpha-catenin for vinculin binding, causing vinculin to relocalize from the cell periphery to internal sites. | Spread | [235] |
Sca4/Rickettsia pakerii | Sca4: Vinculin | Sca4 interaction with vinculin blocks its ability to increase tension and barrier function at cell-cell junctions. | Spread | [236] |
Certhrax/Bacillus cereus | Certhrax: Vinculin | Certhrax interacts with and ADP-ribosylates vinculin at R433 | Spread | [237,238,239] |
FAK | ||||
Tat/HIV-1 | Tat | Tat exposure increases phosphorylation of FAK-Y20 and increased FA numbers | Spread | [240] |
TarP/Chlamydia caviae | TarP (LD): FAK | TarP orchestrates signaling through FAK-cdc42-Arp2/3 to induce actin polymerization | Invasion | [241] |
EspC/EPEC | EspC: FAK | Serine protease activity of EspC cleaves FAK | Cell rounding | [107] |
TK (ORF21)/KSHV | TK: FAK | Kinase activity of TK was required for relocalization of pFAK from peripheral FAs to internal sites, increasing cell detachment | Cell rounding | [242] |
ILK | ||||
OspE/Shigella flexneri | OspE: ILK | OspE-ILK localizes to FA, which results in increased FA size and stability, and decreased motility. OspE decreased phosphorylation of ILK targets, FAK and paxillin. OspE is required for efficient Shigella colonization of guinea pig colons. | Adhesion | [243,244] |
EspO1/EHEC | EspO1: ILK | EspO1–1 localizes with ILK and prevents FA disassembly | Adhesion | [245] |
Talin | ||||
Tir/EPEC | Tir: Talin | Actin polymerization at EPEC adherence site | Invasion | [246] |
IpaA/Shigella flexneri | IpaA: Talin | IpaA recruits talin to coat Shigella at invasion sites, and leads to the formation of extra long filopodia. | Invasion | [247] |
Zyxin | ||||
E6/HPV-6 | E6: Zyxin | E6 interaction with LIM3 domain of zyxin increases its nuclear translocation. | Unknown | [159] |
Src | ||||
E4orf4/Adenovirus 2 | E4:c-Src | Modulation of Src kinase activity increases phosphorylation of coractin and leads to decreased phosphorylation of FAK and paxillin. | Cell death | [109] |
E4orf4 interaction with c-Src increases phosphorylation of MLC. E4orf4-Src localize to juxtanuclear actin complex that involves Rho GTPases. | Cell death | [111] | ||
CagA/Helicobacter pylori | CagA: Src | Src phosphorylates CagA, then phosphorylated CagA inhibits the catalytic activity of Src. Vinculin does not get phosphorylated and lamellipodia formation is reduced. | Spread | [199] |
RhoA | ||||
EspM2/EHEC | EspM2: RhoA | GEF activity of EspM2 activates RhoA-ROCK-LIMK signaling, increasing stress fiber and FA formation. | Spread | [248] |
EspM2: RhoA | EspM2 increases extrusion of cells and causes a redistribution of B1-integrin and ZO-1/tight junctions in a RhoA-dependent manner | Spread | [249] | |
EspO1-2/EHEC | EspO1-2: EspM2 | Suppresses EspM2 activity, preventing RhoA activation and cell contraction | Adhesion | [245] |
EspG and Orf3/ EPEC | EspG: tubulin | Causes microtubule destabilization which releases the H1-GEF and in turn activates RhoA and increases stress fiber formation. | Adhesion | [245] |
E7/HPV-16 | E7(CR3): p190RhoGAP | Interaction wtith p190RhoGAP, a RhoA inhibiting hydrolase decreased F-actin levels and cell area in transfected cells. | Adhesion | [250] |
Genetic Alterations | |||
---|---|---|---|
FA-Associated Protein | Mutation/Deletion | Phenotype | References |
RhoA | T19N | Dominant negative | [292] |
RhoA | V14 | Constitutively active | [293] |
Src | K297M | Kinase-inactive | [207] |
Src | K297M, Y529F | Dominant negative | [294] |
Src | Y527F | Constitutively active | [294] |
FAK | Y397F | Constitutively active; Cannot be auto-phosphorylated | [125] |
FAK | D562A | Kinase-inactive | [216] |
FAK | K464R | Kinase-inactive | [216] |
FRNK | C-terminal domain | Dominant negative—blocks kinase activity and autophosphorylation of Y397 | [295] |
Talin1 | L325R (FERM domain) | Compromises ability of talin1 to activate integrins without affecting binding to the NPxY motif | [296] |
Talin1 | R2526G | Blocks talin1 dimerization and reduces activity of C-terminal actin-binding site | [297] |
Talin1 | L432G | Resistant to calpain2 cleavage | [89] |
Talin1 | E1770A | Constitutively active; F3-R9 interaction disrupted | [117] |
RIAM | E60A/D63A | Constiutively active; Disrupts inhibitory region (IN) and RA domain interaction | [123] |
Vinculin | “T12” and “T12K” | Constitutively active; Destabilize vinculin head-tail interaction | [120,121] |
Cortactin | W22A (NTA domain) | Cannot bind Arp2/3 complex | [298] |
Cortactin | W525K (SH3 domain) | Impaired dynamin binding | [299] |
Zyxin | S142D | Constitutively active; Disrupts interaction between ActA and LIM regions | [127] |
α-actinin | “NEECK” | Constitutively active | [128] |
Chemical inhibitors for investigating FA signaling and dynamics | |||
Inhibitor | Target | Function inhibited | Reference |
Y27632 | ROCK | Competes with ATP for binding to ROCK’s catalytic site | [300] |
Blebbistatin | Myosin II | Inhibits myosin ATPase activity | [301] |
Genistein | Protein Tyrosine Kinases | Inhibits signaling molecules within the Receptor-MAPK or Receptor-PI3K/AKT cascades | [302] |
PP2 | Src | Selectively inhibits Src-family kinases | [303] |
SU6656 | Src | Broadly inhibits Src-family kinases | [304] |
PF 573882 | FAK | Targets FAK catalytic activity by interaction with ATP-binding pocket; blocks Y397 phosphorylation | [305] |
Cytochalaisin D | Actin | Inhibits actin polymerization by preventing actin-cofilin interaction | [306] |
Latrunculin B | Actin | Inhibits actin polymerization by sequestering G-actin | [307] |
Jasplakinolide | Actin | Induces actin polymerization and stabilizes F-actin | [308] |
Wikostatin | N-WASP | Stabilizes N-WASP in its autoinhibited state | [309] |
Leptomycin B | CRM1-mediated translocation | Inhibits the export of proteins from the nucleus to the cytoplasm | [138] |
Established cell lines | |||
Name of cell line | Deletion | Phenotype | Reference |
MEF | FAK | Larger and more numerous focal adhesions; Reduced cell motility | [310] |
MEF/ASML | Vinculin | Reduction in directionally persistent migration and traction force generation | [311] |
MEF/Mouse ES | Talin1 | Unable to assemble vinculin or paxillin containing focal adhesions | [312] |
MEF | Src, Yes, Fyn | Reduction in the tyrosine phosphorylation levels of FAK, p130Cas and paxillin | [313] |
Mouse ES Cells | ILK | Impaired cell spreading and delayed formation of adhesions | [314] |
MEF | Paxillin | Decreased cell spreading and migration; Abnormal FAs; Inefficient localization and phosphorylation of FAK | [315] |
MEF | Zyxin | Reduced Ena/VASP proteins at adhesion sites; Increased motility; Deficits in actin stress fiber remodeling | [316] |
MEF | p130Cas | Slow disassembly of focal adhesions at the cell front | [48] |
PMNs | RIAM | Defects in adherence and cell spreading; Impaired activation of β2 integrins | [317] |
GD25 (mouse) | β1-integrin | Low level of attachment to ECM substrates | [318] |
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Murphy, K.N.; Brinkworth, A.J. Manipulation of Focal Adhesion Signaling by Pathogenic Microbes. Int. J. Mol. Sci. 2021, 22, 1358. https://doi.org/10.3390/ijms22031358
Murphy KN, Brinkworth AJ. Manipulation of Focal Adhesion Signaling by Pathogenic Microbes. International Journal of Molecular Sciences. 2021; 22(3):1358. https://doi.org/10.3390/ijms22031358
Chicago/Turabian StyleMurphy, Korinn N., and Amanda J. Brinkworth. 2021. "Manipulation of Focal Adhesion Signaling by Pathogenic Microbes" International Journal of Molecular Sciences 22, no. 3: 1358. https://doi.org/10.3390/ijms22031358