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Aberrant Splicing of Cyclin-Dependent Kinase–Associated Protein Phosphatase KAP Increases Proliferation and Migration in Glioblastoma

Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Mark D. Johnson, Department of Neurological Surgery, Brigham and Women's Hospital, Boston, MA 02115. Phone: 617-732-6952; Fax: 617-734-8342; E-mail: mjohnson27{at}partners.org.

The cyclin-dependent kinase (Cdk)–associated protein phosphatase KAP is a dual-specificity phosphatase of which the only known function is to dephosphorylate Cdk2 and inhibit cell cycle progression. Paradoxically, we find increased KAP mRNA expression in malignant astrocytomas, which correlates with increasing histologic grade and decreased patient survival. We have resolved this apparent paradox with the discovery of aberrant KAP splicing in malignant astrocytomas that leads to increased expression of KAP-related transcripts but decreased KAP protein expression. In addition, the aberrant splicing generates a dominant negative KAP variant that increases proliferation. We provide the first evidence that KAP not only regulates proliferation but also inhibits migration by decreasing cdc2 mRNA and protein expression. The effect of KAP on cdc2 expression requires its phosphatase activity but does not involve direct dephosphorylation of cdc2. Thus, KAP regulates both cdc2-dependent migration and Cdk2-dependent proliferation, and its loss due to aberrant splicing increases malignancy in human gliomas. [Cancer Res 2006;67(1):130–8]

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