School of Molecular Sciences - Arizona State University
Host: Adam Barb
"Understanding the Versatile Cytokine Pleiotrophin"
Pleiotrophin (PTN) is a versatile cytokine involved in neural development, tissue regeneration, inflammation and cancer metastasis. It has a high affinity for the polysaccharide glycosaminolglycan (GAG) found on proteoglycan receptors, but is also known to bind non-proteoglycan receptors. Despite its importance in biology, very little is known about structural interactions of PTN with these receptors.
We have determined the structure of PTN and studied PTN’s interactions with GAG and identified the PTN receptor on macrophages. Our results indicate PTN is a promiscuous GAG-binding protein with affinity for many types of GAGs. However, despite having two independent GAG-binding domains, PTN is unable to crosslink GAG chains on different receptors. In addition, different basic amino acid clusters in PTN contribute to GAG binding differently. Specifically, one cluster in the C-terminal TSR domain does not contribute to GAG binding substantially but is vital to protein folding. Our work also identified Mac-1 as a novel PTN receptor on macrophages.
Our analysis shows PTN can induce Mac-1 dependent adhesion and migration in both HEK293 cells and mouse macrophages. Examination of kinase phosphorylation levels shows PTN-binding to Mac-1 activates the kinase ERK1/2, an important kinase involved in the activation of macrophages.
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