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Bartosz Pilecki Institute of Molecular Medicine, Odense, Denmark 27.09.2015

Microfibrillar-associated protein 4 is a novel regulator of elastic fiber assembly and integrin-dependent cellular signaling. Bartosz Pilecki Institute of Molecular Medicine, Odense, Denmark 27.09.2015 5th FEBS MPSMT Course, Rhodes. Elastic fibers. Large insoluble ECM structures

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Bartosz Pilecki Institute of Molecular Medicine, Odense, Denmark 27.09.2015

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  1. Microfibrillar-associated protein 4 is a novel regulator of elastic fiber assembly and integrin-dependent cellular signaling Bartosz Pilecki Institute of Molecular Medicine, Odense, Denmark 27.09.2015 5th FEBS MPSMT Course, Rhodes

  2. Elastic fibers • Large insoluble ECM structures • Provide recoil to tissues undergoing repeated stretch (arteries, lung, skin) • Composed of inner elastin core and microfibril scaffold

  3. Elastic fiber assembly Wise and Weiss, Int J Biochem Cell BIol 2009

  4. MFAP4 • ECM protein of a fibrinogen-related domain (FReD) family (tenascins, angiopoietins, ficolins) • Abundant in elastin-rich tissues • Ultrastructurally located at elastin-microfibril interface (Toyoshima et al., J Histochem Cytochem 1999) Wulf-Johansson et al., PLoS One 2013

  5. MFAP4 • Interacts with fibrillin-1 and contributes to skin photoprotection (Kasamatsu et al., Sci Rep 2011) • Contains N-terminal RGD sequence • Promotes proliferation and migration of vascular SMC in an integrin-dependent manner – potential implications in asthma (BSMC proliferation and cytokine secretion implicated)

  6. MFAP4-deficient mice develop emphysema-like changes Holm et al., Am J Physiol Lung Cell Mol Physiol 2015

  7. Aims • To characterize molecular interactions between MFAP4 and elastic fiber components • To investigate the role of MFAP4 in integrin-dependent signaling in human bronchial smooth muscle cells (BSMCs)

  8. MFAP4 binds fibrillin-1 and fibrillin-2

  9. MFAP4 binds tropoelastin

  10. MFAP4 promotes tropoelastin self-assembly

  11. MFAP4 and integrin expression in BSMCs Pilecki et al., Thorax 2015

  12. MFAP4 promotes BSMC adhesion through integrin alphavbeta5 Pilecki et al., Thorax 2015

  13. MFAP4 promotes BSMC proliferation and eotaxin expression Pilecki et al., Thorax 2015

  14. Conclusions: • MFAP4 interacts with fibrillins and tropoelastin • MFAP4 promotes tropoelastin coacervation • MFAP4 is upregulated in asthmaticBSMCs • MFAP4 mediatesproliferationand eotaxinproductionin asthmaticBSMCsthroughintegrin alphavbeta5/PI3K pathway Our data suggest that MFAP4 is an important regulator of elastic fiber formation and homeostasis as well as airway smooth muscle biology.

  15. Acknowledgements IMM, Odense Grith L. Sorensen Uffe Holmskov Soren Moestrup University of Cologne, Germany Gerhard Sengle Alexander Vohl Stefanie Heumuller Fonden til Laegevidenskabens Fremme Aase og Ejnar Danielsens Fond J. og O. Madsens Fond Linex Fonden

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