FIZZ1, also cared hypoxia-induced mitogenic factor (HIMF), is a resistin-like molecule that is up-regulated in the murine models of chronic hypoxia lung and acute pulmonary inflammation as well as in the normal lymph nodes.In order to investigate the signaling pathway of FIZZ1 and its disease-related function, we established bone marrow stem cell culture and transplant systems, lung hypoxia model and fluo-4 based measurement of intracellular calcium ([Ca2+]i) for the study.By using GST-pulldown and mass spectrometry analysis, we found Brutons tyrosine kinase(BTK) to be a FIZZl-binding partner.FIZZ1 stimulated leukocyte migration in vitro and in vivo, and a selective BTK inhibitor blocked the stimulation of FIZZ 1 in cell migration.FIZZ1 acts as a chemotactic molecule in stimulating the migration of leukocytes through activation of the BTK pathway.The results from bone marrow transplantation experiments showed that FIZZ1 is involved in recruiting bone marrow stem cells into lung tissue.Intracellular calcium ([Ca2+]i) based on fluo-4 measurement demonstrated that recombinant murine FIZZ1 increased [Ca2+]i in human pulmonary artery smooth muscle cells (HPASMC).The increase in [Ca2+]i after FIZZ1 exposure was independent of extracellular calcium influx, suggesting the involvement of internal stores.The increase in [Ca2+]i in HPASMC was also abolished by pretreatment with 2-aminoethoxydiphenyl borate (2-APB), an IP3 receptor antagonist, but not ryanodine, the ryanodine receptor antagonist.Pretreatment with the Gαi-specific inhibitor, pertussis toxin, had no effect on calcium signal.However, pretreatment with the tyrosine kinase inhibitor genistein completely inhibited the internal calcium release, suggesting a role for tyrosine phosphorylation in the [Ca2+]i response.