Fig. 6
A summary of the proposed CathL-induced Gal1 secretion pathway and its pro-proliferative function and potential therapeutic targets in HOMECS. 1. CathL non-proteolytically activates a cell surface receptor, possibly a receptor tyrosine kinase, which leads to an increase in activated levels of the transcription factor NFÎşB, resulting in increased expression of LGALS1 (Gal1 mRNA). Sulfasalazine, an inhibitor of NFÎşB, reduces LGALS1 expression and subsequent secreted level of Gal1. 2. LGALS1 is transcribed and translated into Gal1 which is secreted out of the cell, possibly utilising a Na+/K+ ATP-pump, via a non-conventional secretory pathway. 3. Secreted Gal1 induces activation of MAP kinase ERK1/2 and PI3K/AKT via an autocrine mechanism and an unknown receptor(s), where the ERK1/2 pathway induces HOMEC proliferation. The MEK/ERK1/2 inhibitors U0126 and PD98059 significantly reduce this cellular function by inhibiting ERK1/2 phosphorylation. Both the PI3K inhibitor LY294002 and AKT inhibitor MK2206 inhibit phosphorylation of AKT at Ser473 (S473) in Gal1-treated HOMECs. However, only LY294002, but not MK2206, inhibits Gal1-induced HOMEC proliferation, suggesting a cross-reactivity of PI3K inhibitor LY294002 with the ERK1/2 pathway. Potential therapeutic targets are: Gal1 secretory mechanism, Gal1 binding to its receptor(s), and blocking receptor(s) for Gal1. N, nucleus; C, cytoplasm