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
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. Wulf-Johansson et al., PLoS One 2013
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 asthmatic BSMCs
MFAP4 mediates proliferation and eotaxin production in asthmatic BSMCs through integrin 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. University of Cologne, Germany
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