Characterization of a role of 5-diphosphoinositol pentakisphosphate in the regulation of ERBB4 signaling pathway

Abstract

5-Diphosphoinositol pentakisphosphate (5-IP7) is an endogenous metabolite that regulates a myriad of cellular functions. Recently, there have been increasing evidences that 5-IP7 inhibits tumor growth and cancer cell proliferation. The regulatory function of 5-IP7 in cancer, however, still remains elusive. Here I propose ERBB4 as a novel target protein of 5-IP7, which is one of the essential protein kinases involved in cell growth and proliferation. Biochemical assays, such as cellular thermal shift assay and in vitro kinase assay, revealed that 5-IP7 bound ERBB4 in cell lysate and inhibited ERBB4 kinase activity in vitro. Moreover, overexpression of IP6K1 significantly diminished ERBB4 kinase activity in cells and impeded ERBB4 downstream signaling events. In this thesis, these novel findings collectively imply that 5-IP7 is the crucial metabolite involved in the regulation of cancer growth via metabolite-protein interaction with ERBB4, rendering novel perspectives in development of anti-cancer drugs and therapeutics.