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@PHDTHESIS{Andrzejewski:51388,
      author       = {Andrzejewski, Michael G.},
      othercontributors = {Ludwig, Andreas},
      title        = {{R}equirements for cleavage and function of the
                      transmembrane chemokine fractalkine/{CX}3{CL}1},
      address      = {Aachen},
      publisher    = {Publikationsserver der RWTH Aachen University},
      reportid     = {RWTH-CONV-113684},
      pages        = {III, 110 S. Ill., graph. Darst.},
      year         = {2009},
      note         = {Aachen, Techn. Hochsch., Diss., 2009},
      abstract     = {Leukocytes are recruited from the blood vessel wall towards
                      the inflamed tissue. This process occurs in multiple steps
                      and is regulated in part by chemokines. Among the large
                      family of chemokines that mediate directional cell migration
                      an unusual member the CX3CL1 (fractalkine) is described
                      existing as a transmembrane and a soluble molecule. The
                      generation of this soluble CX3CL1 molecule occurs upon
                      ectodomain shedding by metalloproteinases, in particular by
                      ADAM10. By binding to the receptor CX3CR1 the transmembrane
                      CX3CL1 mediates adhesion and transmigration of leukocytes
                      subpopulations. Up to date, it is not clear how ADAM10
                      contributes to the function of mouse CX3CL1. The goal of
                      this thesis was to characterise the molecular determinants
                      of mouse CX3CL1 for shedding and function of this molecule.
                      Results of this study demonstrated that mouse CX3CL1 is
                      predominately shed by ADAM10-dependent mechanisms as shown
                      by pharmacological inhibition and transcriptional silencing.
                      As described for human CX3CL1, shedding of mouse CX3CL1 is
                      enhanced by ionomycin treatment, which also involves
                      ADAM10-activity. Deletion and replacement of the cleavage
                      region of mouse CX3CL1 could not further abrogate its
                      release suggesting that other domains of mouse CX3CL1 may
                      influence this process. And indeed, release of mouse CX3CL1
                      was found to be further influenced by the chemokine domain
                      and also the cytoplasmic tail. However, truncation of the
                      cytoplasmic tail led also to impaired cellular trafficking.
                      In fact, when wt mouse CX3CL1 and the truncated variant were
                      sufficiently expressed on the cell surface, both were still
                      shed. Additionally, adhesion and transmigration experiments
                      with human PBMCs revealed that the truncation did not affect
                      the function of the transmembrane mouse CX3CL1 as an
                      adhesion and a transmigration molecule. This latter finding
                      suggests that potential signalling events induced by the
                      cytoplasmic tail of CX3CL1 are not involved in the
                      recruitment of leukocytes to the inflamed tissue. This work
                      indicates that multiple molecular determinants within mouse
                      CX3CL1 influence its shedding via ADAM10, suggesting that
                      exchange of several domains of mouse CX3CL1 cannot
                      completely prevent its shedding. The cytoplasmic tail of
                      mouse CX3CL1 appears to be relevant for correct trafficking
                      of mouse CX3CL1 but neither for shedding, adhesion or
                      transmigration. Nevertheless, shedding of CX3CL1 by ADAM10
                      and ADAM17 could still represent a crucial step within the
                      leukocyte recruitment process in developing vascular
                      diseases such as atherosclerosis.},
      keywords     = {Proteolyse (SWD)},
      cin          = {528500-2},
      ddc          = {570},
      cid          = {$I:(DE-82)528500-2_20140620$},
      typ          = {PUB:(DE-HGF)11},
      urn          = {urn:nbn:de:hbz:82-opus-31142},
      url          = {https://publications.rwth-aachen.de/record/51388},
}