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

Kozlova, N.; Mennerich, D.; Samoylenko, A.; Dimova, E. Y.; Koivunen, P.; Biterova, E.; Richter, K.; Hassinen, A.; Kellokumpu, S.; Manninen, A.; Miinalainen, I.; Glumoff, V.; Ruddock, L.; Drobot, L.; Kietzmann, T.

doi:10.1101/466946

bioRxiv · 10.1101/466946

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

Kozlova, N.·Mennerich, D.·Samoylenko, A.·Dimova, E. Y.·Koivunen, P.·Biterova, E.·Richter, K.·Hassinen, A.·Kellokumpu, S.·Manninen, A.·Miinalainen, I.·Glumoff, V.·Ruddock, L.·Drobot, L.·Kietzmann, T.

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Abstract

The EGFR-adaptor protein CIN85 has been shown to promote breast cancer malignancy and hypoxia-inducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill-defined. Here, we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SH3 domains of CIN85 interact with the proline-arginine rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF-degradation. This activity is essential in vivo, as specific loss of the CIN85-PHD2 interaction in CRISPR/Cas9 edited cells affected growth and migration properties as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2, and uncovered an essential survival function in tumor cells linking growth factor adaptors with hypoxia signaling.

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Kozlova, N., Mennerich, D., Samoylenko, A., Dimova, E. Y., Koivunen, P., Biterova, E., Richter, K., Hassinen, A., Kellokumpu, S., Manninen, A., Miinalainen, I., Glumoff, V., Ruddock, L., Drobot, L., Kietzmann, T.. 2018-11-09. The pro-oncogenic adaptor CIN85 inhibits hypoxia-inducible factor prolyl hydroxylase-2. https://doi.org/10.1101/466946

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