Contribution of Crk Adaptor Proteins to Host Cell and Bacteria Interactions

Martı́nez-Quiles, Narcisa; Feuerbacher, Leigh Ann; Benito-León, María; Hardwidge, Philip R.

doi:10.1155/2014/372901

Cited by 9 publications

(12 citation statements)

References 121 publications

(142 reference statements)

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“…Crk has been shown to function in various host defenses against bacterial pathogens, such as inhibiting EPEC-induced actin-based pedestal formation, increasing bacterial clearance through phagocytosis of IgG-opsonized pathogens by Fcγ receptors, and potentially enhancing innate immune activation through pattern recognition receptors (PRR) by sequestering bacterial virulence factors, such as EPEC’s Tir, which interfere with PRR signaling [ 63 – 65 ]. Therefore, it is not surprising that pathogens have evolved mechanisms to target this central host protein in order to advance their own agenda.…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa ExoT Induces Atypical Anoikis Apoptosis in Target Host Cells by Transforming Crk Adaptor Protein into a Cytotoxin

2015

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Previously, we demonstrated that Pseudomonas aeruginosa ExoT induces potent apoptosis in host epithelial cells in a manner that primarily depends on its ADP-ribosyltransferase domain (ADPRT) activity. However, the mechanism underlying ExoT/ADPRT-induced apoptosis remains undetermined. We now report that ExoT/ADPRT disrupts focal adhesion sites, activates p38β and JNK, and interferes with integrin-mediated survival signaling; causing atypical anoikis. We show that ExoT/ADPRT-induced anoikis is mediated by the Crk adaptor protein. We found that Crk-/- knockout cells are significantly more resistant to ExoT-induced apoptosis, while Crk-/- cells complemented with Crk are rendered sensitive to ExoT-induced apoptosis. Moreover, a dominant negative (DN) mutant form of Crk phenocopies ExoT-induced apoptosis both kinetically and mechanistically. Crk is generally believed to be a component of focal adhesion (FA) and its role in cellular survival remains controversial in that it has been found to be either pro-survival or pro-apoptosis. Our data demonstrate that although Crk is recruited to FA sites, its function is likely not required for FA assembly or for survival per se. However, when modified by ExoT or by mutagenesis, it can be transformed into a cytotoxin that induces anoikis by disrupting FA sites and interfering with integrin survival signaling. To our knowledge, this is the first example whereby a bacterial toxin exerts its cytotoxicity by subverting the function of an innocuous host cellular protein and turning it against the host cell.

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Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa ExoT Induces Atypical Anoikis Apoptosis in Target Host Cells by Transforming Crk Adaptor Protein into a Cytotoxin

2015

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“…This is likely to be of relevance during Bordetella infections, as hijacking of Crk appears to be implicated in bacterial pathogenesis through diverse mechanisms, including subversion of cellular ruffle formation (reviewed in Martinez-Quiles et al . 75 ). The Crk-associated proteins retained in the interaction network (c.f.…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomics of cAMP signaling of Bordetella adenylate cyclase toxin in mouse dendritic cells

Novák

Fabrik

Linhartová

et al. 2017

Sci Rep

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The adenylate cyclase toxin (CyaA) of the whooping cough agent Bordetella pertussis subverts immune functions of host myeloid cells expressing the αMβ2 integrin (CD11b/CD18, CR3 or Mac-1). CyaA delivers into cytosol of cells an extremely catalytically active adenylyl cyclase enzyme, which disrupts the innate and adaptive immune functions of phagocytes through unregulated production of the key signaling molecule cAMP. We have used phosphoproteomics to analyze cAMP signaling of CyaA in murine bone marrow-derived dendritic cells. CyaA action resulted in alterations of phosphorylation state of a number of proteins that regulate actin cytoskeleton homeostasis, including Mena, Talin-1 and VASP. CyaA action repressed mTOR signaling through activation of mTORC1 inhibitors TSC2 and PRAS40 and altered phosphorylation of multiple chromatin remodelers, including the class II histone deacetylase HDAC5. CyaA toxin action further elicited inhibitory phosphorylation of SIK family kinases involved in modulation of immune response and provoked dephosphorylation of the transcriptional coactivator CRTC3, indicating that CyaA-promoted nuclear translocation of CRTC3 may account for CyaA-induced IL-10 production. These findings document the complexity of subversive physiological manipulation of myeloid phagocytes by the CyaA toxin, serving in immune evasion of the pertussis agent.

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“…Signals are usually received by transmembrane receptors (e.g., receptor tyrosine kinases [RTKs], integrins, or cadherins), and signal transduction is often initiated by the formation of multiprotein complexes associated with receptor cytoplasmic tails. Small adapter proteins such as Grb2, Crk, or Nck play critical roles in both signal amplification and specificity (e.g., Lettau et al ., 2009; Belov and Mohammadi, 2012; Martinez-Quiles et al ., 2014). They confer signal specificity by using Src homology domain 2 (SH2) and 3 (SH3) or other protein interaction domains to physically link activated receptors and downstream effectors.…”

Section: Introductionmentioning

confidence: 99%

The Crk adapter protein is essential forDrosophilaembryogenesis, where it regulates multiple actin-dependent morphogenic events

Spracklen

Thornton-Kolbe

Bonner

et al. 2019

MBoC

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Small Src homology domain 2 (SH2) and 3 (SH3) adapter proteins regulate cell fate and behavior by mediating interactions between cell surface receptors and downstream signaling effectors in many signal transduction pathways. The CT10 regulator of kinase (Crk) family has tissue-specific roles in phagocytosis, cell migration, and neuronal development and mediates oncogenic signaling in pathways like that of Abelson kinase. However, redundancy among the two mammalian family members and the position of the Drosophila gene on the fourth chromosome precluded assessment of Crk’s full role in embryogenesis. We circumvented these limitations with short hairpin RNA and CRISPR technology to assess Crk’s function in Drosophila morphogenesis. We found that Crk is essential beginning in the first few hours of development, where it ensures accurate mitosis by regulating orchestrated dynamics of the actin cytoskeleton to keep mitotic spindles in syncytial embryos from colliding. In this role, it positively regulates cortical localization of the actin-related protein 2/3 complex (Arp2/3), its regulator suppressor of cAMP receptor (SCAR), and filamentous actin to actin caps and pseudocleavage furrows. Crk loss leads to the loss of nuclei and formation of multinucleate cells. We also found roles for Crk in embryonic wound healing and in axon patterning in the nervous system, where it localizes to the axons and midline glia. Thus, Crk regulates diverse events in embryogenesis that require orchestrated cytoskeletal dynamics.

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Contribution of Crk Adaptor Proteins to Host Cell and Bacteria Interactions

Cited by 9 publications

References 121 publications

Pseudomonas aeruginosa ExoT Induces Atypical Anoikis Apoptosis in Target Host Cells by Transforming Crk Adaptor Protein into a Cytotoxin

Pseudomonas aeruginosa ExoT Induces Atypical Anoikis Apoptosis in Target Host Cells by Transforming Crk Adaptor Protein into a Cytotoxin

Phosphoproteomics of cAMP signaling of Bordetella adenylate cyclase toxin in mouse dendritic cells

The Crk adapter protein is essential forDrosophilaembryogenesis, where it regulates multiple actin-dependent morphogenic events

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