Editors' ChoiceCancer

Protein homeostasis limiting cancer

Sci. Signal.  19 Jan 2016:
Vol. 9, Issue 411, pp. ec12
DOI: 10.1126/scisignal.aaf2516

There is interest in targeting protein quality control pathways that ensure refolding or elimination of misfolded proteins to kill cancer cells. Osorio et al. identified a role for AIRAPL (an ortholog of AIP-1, which is involved in protein quality control pathways in Caenorhabditis elegans) in myeloproliferative neoplasms, a group of diseases in which the production of blood cells in the bone marrow is increased. Mice lacking Zfand2b (the gene encoding AIRAPL) developed hematological symptoms characteristic of myeloproliferative neoplasms, such as splenomegaly and expansion of various myeloid lineages. Western blot analysis of bone marrow from Zfand2b–/– mice revealed an increase in the total abundance and phosphorylation of insulin/insulin-like growth factor 1 receptor (IGF1R), a kinase that activates cell growth and proliferation. In HEK-293T cells, overexpression of AIRAPL reduced IGF1R abundance in a proteasome-dependent manner. Furthermore, exogenous AIRAPL interacted with pro-IGF1R rather than mature IGF1R, and knockout of endogenous AIRAPL resulted in an increase in the abundance of mature IGF1R, suggesting that AIRAPL triggered the proteasomal degradation of pro-IGF1R before it could undergo processing to the mature form. Igf1r haploinsufficiency in Zfand2b–/– mice or treatment of Zfand2b–/– mice with a kinase inhibitor of IGF1R prevented or attenuated the development of hematological symptoms seen in Zfand2b–/– mice. In addition, hematological symptoms were improved in mice that are a model of a specific type of myeloproliferative neoplasm upon treatment with an IGF1R kinase inhibitor or transduction with bone marrow cells from Igf1r+/+ mice (but not with that from Igf1r+/– mice). In samples from individuals with various types of myeloproliferative neoplasms, AIRAPL was not detected and both pro- and mature IGF1R were increased in abundance. Thus, AIRAPL limits the processing of IGF1R into its mature form in hematopoietic stem cells and thus the production of myeloid cells. These results also suggest that IGF1R inhibitors could be used in combination with existing therapies for myeloproliferative neoplasms (see LaFave and Levine).

F. G. Osorio, C. Soria-Valles, O. Santiago-Fernández, T. Bernal, M. Mittelbrunn, E. Colado, F. Rodríguez, E. Bonzon-Kulichenko, J. Vázquez, M. Porta-de-la-Riva, J. Cerón, A. Fueyo, J. Li, A. R. Green, J. M. P. Freije, C. López-Otín, Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling. Nat. Med. 22, 91–96 (2016). [PubMed]

L. M. LaFave, R. L. Levine, Targeting a regulator of protein homeostasis in myeloproliferative neoplasms. Nat. Med. 22, 20–21 (2016). [PubMed]