Rin1 is a negative regulator of the IL3 receptor signal transduction pathways

Cytokines interact with cell-surface receptors, initiating signaling cascades that promote cell growth while inhibiting the pathways of apoptotic cells. Rin1 is a multifunctional protein that has been shown to regulate EGF receptor signaling and endocytosis. To examine the role of Rin1 in IL3 receptor signaling pathways, Rin1 and deletion mutants were expressed in cells using a retrovirus system. In this study, the overexpression of Rin1 molecules was shown to selectively block IL-3 activation of the Ras-Erk1/2 and PI3K/Akt pathways and the IL-3-stimulated incorporation of [3H] thymidine into DNA without a significant effect on the activity of the JNK and p38K pathways. Moreover, the depletion of Rin1 by RNA interference induced cell growth. In addition, Rin1 was also required as a downstream effector of BCR/ABL-induced cell proliferation. Interestingly, the expression of Rin1 selectively blocked the activation of Erk1/2 induced by the BCR/ABL oncogene. These results demonstrate that Rin1 plays an essential and selective role in both IL3- and BCR/ABL-induced cell proliferation and highlight a new function for Rin1 in leukemic cells.