Thromboxane A2-induced signal transduction is negatively regulated by KIAA1005 that directly interacts with thromboxane A2 receptor

Thromboxane A2 (TXA2), a potent inducer of platelet aggregation and smooth muscle contraction, exerts its action through TXA2 receptor (TP). There are two alternative splicing variants of TP, TPα and TPβ. To clarify the signal transduction of TP pathway, we searched for putative TP binding proteins using a yeast two-hybrid system with the C-terminal region of TPα or TPβ as bait. We found KIAA1005 as a novel interacting protein of the TPα and TPβ C-terminal region (TP interacting protein, TPIP). KIAA1005/TPIP was co-immunoprecipitated with TPα or TPβ in HEK293 cells expressing myc-KIAA1005/TPIP and FLAG-TP isoforms. Expression analysis showed a ubiquitous expression pattern of KIAA1005/TPIP mRNA, including prominent expression in the thymus. Furthermore, TP-mediated phosphoinositide hydrolysis, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and interleukin-6 production were reduced by the expression of KIAA1005/TPIP. The expression of KIAA1005/TPIP decreased cell-surface TPα and TPβ levels. Thus, we show for the first time that KIAA1005/TPIP is a novel TP interacting protein that regulates TP-mediated signal transduction negatively.