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Bruton’s tyrosine kinase (BTK) is a binding partner for hypoxia induced mitogenic factor (HIMF/FIZZ1) and mediates myeloid cell chemotaxis

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

¹Correspondence: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Ross 361, 720 Rutland Ave., Baltimore, MD 21205, USA. E-mail: rajohns{at}jhmi.edu

Hypoxia induced mitogenic factor (HIMF) is a member of the FIZZ/resistin/RELM family of proteins that we have shown to have potent mitogenic, angiogenic, and vasoconstrictive effects in the lung vasculature. In the current report, we identified Bruton’s tyrosine kinase (BTK) as a functional HIMF binding partner through glutathione S-transferase (GST)-HIMF pull-down studies and mass spectrometry. Using primary cultured HIMF-stimulated murine bone marrow cells, we demonstrated that HIMF causes redistribution of BTK to the leading edge of the cells. HIMF stimulation induced BTK autophosphorylation, which peaked at 2.5 min. A transwell migration assay showed that treatment with recombinant murine HIMF induced migration of primary cultured bone marrow cells that was completely blocked by the BTK inhibitor, LFM-A13. Our results demonstrate BTK as the first known functional binding partner of the HIMF/FIZZ family of proteins and that HIMF acts as a chemotatic molecule in stimulating the migration of myeloid cells through activation of the BTK pathway.—Su, Q., Zhou, Y., and Johns, R. A. Bruton’s tyrosine kinase (BTK) is a binding partner for hypoxia induced mitogenic factor (HIMF/FIZZ1) and mediates myeloid cell chemotaxis.

Key Words: resistin • LFM-A13 • migration