Extracellular Hsp70 stimulates multiple signaling pathways in A431 carcinoma cells

Abstract

Heat shock proteins (Hsp) were considered to be intracellular. However, there is evidence that stress-inducible Hsp70 is released by cells into the blood or conditioned medium of cultured cells. Previously the signaling function of exogenously added Hsp70 was proposed, referred to as chaperone function of Hsp70. The later was restricted to immune cells. Here we show that Hsp70 stimulates TLR2/4 receptors in A431 squamous carcinoma cells. Extracellular Hsp70 secreted at the initial steps of heat shock is shown to be sufficient for the EGF receptor (EGFR) transactivation. The recombinant Hsp70 stimulates tyrosine phosphorylation of EGFR and the appearance of phosphorylated forms of key components of its downstream signaling pathways: phospholipase Cγ1 (PLCγ1), transcription factor STAT3, and ERK1/2. The neutralizing antibody to EGFR has no effect on the Hsp70-induced EGFR activation, which suggests that neither extracellular Hsp70 nor other extracellular factor binds to EGFR.