Thromboxane A(2) (TXA(2)), a potent inducer of platelet aggregation and smooth muscle contraction, exerts its action through TXA(2) receptor (TP). There are two alternative splicing variants of TP, TP alpha and TP beta. 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 TP alpha or TP beta as bait. We found KIAA1005 as a novel interacting protein of the TP alpha and TP beta C-terminal region (TP interacting protein, TPIP). KIAA1005/TPIP was co-immunoprecipitated with TP alpha or TP beta 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 TP alpha and TP beta levels. Thus, we show for the first time that KIAA1005/TPIP is a novel TP interacting protein that regulates TP-mediated signal transduction negatively.