The pro-oncogenic adaptor CIN85 inhibits hypoxia-inducible factor prolyl hydroxylase-2

The family of HIF-prolyl hydroxylases is crucially involved in the regulation of hypoxia-inducible factor (HIF) levels. We have previously shown that the EGFR-adaptor protein CIN85 promotes breast cancer malignancy and HIF-1α stability. These findings suggested that the CIN85-mediated effects occur via interference of proline hydroxylase (PHD)-dependent HIF-α protein degradation and involve a molecular association between CIN85 and PHDs. Indeed, our current study identified CIN85 as a novel binding partner of the main HIF-prolyl hydroxylase PHD2, but not of PHD1 or PHD3. We defined the importance of the N-terminal SH3 domains of CIN85 and the proline-arginine rich region within the amino acids 77-100 in the N-terminus of PHD2 for CIN85-PHD2 complex formation.