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  • Mechanisms of PAR-1 mediated kinase receptor transactivation: Smad linker region phosphorylation

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    Accepted Manuscript (AM)
    Author(s)
    Kamato, Danielle
    Ta, Hang
    Afroz, Rizwana
    Xu, Suowen
    Osman, Narin
    Little, Peter J
    Griffith University Author(s)
    Ta, Hang
    Afroz, Rizwana
    Kamato, Danielle
    Year published
    2019
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    Abstract
    Protease activated receptors (PARs) transactivate both epidermal growth factor receptors (EGFR) and transforming growth factor (TGF)-β receptors (TGFBR1) in vascular smooth muscle leading to the increased expression of genes (CHST11 and CHSY1) which are rate limiting for the enzymes that mediate hyperelongation of glycosaminoglycan (GAG) chains on the lipid-binding proteoglycan, biglycan. This is an excellent model to investigate mechanisms of transactivation as the processes are biochemically distinct. EGFR transactivation is dependent on the classical matrix metalloprotease (MMP) based triple membrane bypass mechanism and ...
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    Protease activated receptors (PARs) transactivate both epidermal growth factor receptors (EGFR) and transforming growth factor (TGF)-β receptors (TGFBR1) in vascular smooth muscle leading to the increased expression of genes (CHST11 and CHSY1) which are rate limiting for the enzymes that mediate hyperelongation of glycosaminoglycan (GAG) chains on the lipid-binding proteoglycan, biglycan. This is an excellent model to investigate mechanisms of transactivation as the processes are biochemically distinct. EGFR transactivation is dependent on the classical matrix metalloprotease (MMP) based triple membrane bypass mechanism and TGFBR1 transactivation is dependent on Rho/ROCK signalling and integrins. We have shown that all kinase receptor signalling is targeted towards phosphorylation of the linker region of the transcription factor, Smad2. We investigated the mechanisms of thrombin mediated kinase receptor transactivation signalling using anti-phospho antibodies and Western blotting and gene expression by RT-PCR. Thrombin stimulation of phospho-Smad2 (Ser 245/250/255) and of phospho-Smad2(Thr220) via EGFR transactivation commences quickly and extends out to at least 4 h whereas transactivation via TGFBR1 is delayed for 120 min but also persists for at least 4 h. Signalling of thrombin stimulated Smad linker region phosphorylation is approximately equally inhibited by the MMP inhibitor, GM6001 and the ROCK inhibitor, Y27632, and similarly expression of CHST11 and CHSY1 is approximately equally inhibited by GM6001 and Y27632. The data establishes Smad linker region phosphorylation as a central target of all transactivation signalling of GAG gene expression and thus an upstream kinase may be a target to prevent all transactivation signalling and its pathophysiological consequences.
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    Journal Title
    Journal of Cell Communication and Signaling
    Volume
    13
    Issue
    4
    DOI
    https://doi.org/10.1007/s12079-019-00527-5
    Copyright Statement
    © 2019 Springer Netherlands. This is an electronic version of an article published in the Journal of Cell Communication and Signaling, 13, pages 539–548(2019). The Journal of Cell Communication and Signaling is available online at: http://link.springer.com/ with the open URL of your article.
    Subject
    Biochemistry and cell biology
    Clinical sciences
    Oncology and carcinogenesis
    Science & Technology
    Life Sciences & Biomedicine
    Cell Biology
    Transactivation signalling
    G protein coupled receptors
    Publication URI
    http://hdl.handle.net/10072/396243
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    • Journal articles

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