CELL BIOLOGY AND METABOLISM
Physical and Functional Interactions between Pim-1 Kinase and Cdc25A Phosphatase: IMPLICATIONS FOR THE Pim-1-MEDIATED ACTIVATION OF THE c-Myc SIGNALING PATHWAY*

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The pim-1 oncogene encodes a serine/threonine kinase (Pim-1) involved in the transduction of cytokine-triggered mitogenic signals. Pim-1 is unique in that it closely cooperates with c-Myc not only in oncogenesis, but also in apoptosis induction. However, the molecular basis of Pim-1 function remains poorly understood, largely because the downstream effector molecule(s) for Pim-1 kinase has not been identified. Here we provide several lines of evidence that Cdc25A cell cycle phosphatase, a direct transcriptional target for c-Myc, is a substrate for Pim-1 kinase and functions as an effector for Pim-1. We found that Pim-1 physically interacts with Cdc25A both in vitro and in vivoand phosphorylates Cdc25A. We also observed that Pim-1-mediated phosphorylation of Cdc25A increases its phosphatase activity. In addition, wild-type Pim-1, but not kinase-inactive Pim-1, enhanced Cdc25A-mediated cellular transformation and apoptosis. Our results indicate that Cdc25A might be a key molecule that links Pim-1 and c-Myc and that also ties Pim-1-mediated mitogenic signals to cell cycle machinery.

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This work was supported in part by a grant-in-aid for the Second Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health and Welfare of Japan and by grants for cancer research from the Ministry of Health and Welfare of Japan and from the Ministry of Education, Science, and Culture of Japan (to Y. K. and C. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Recipient of a research resident fellowship from the Foundation for the Promotion of Cancer Research.

© 1999 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.