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Vol. 18, Issue 10, 4190-4199, October 2007

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Nuclear Localization of the ERK MAP Kinase Mediated by Drosophila PS2PS Integrin and Importin-7

Brian P. James^*,, Thomas A. Bunch^*, Srinivasan Krishnamoorthy^,, Lizabeth A. Perkins, and Danny L. Brower^*

*Department of Molecular and Cellular Biology, Center for Insect Science, and Department of Biochemistry and Molecular Biophysics, Arizona Cancer Center, Tucson, AZ 85724; and Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115

Submitted August 1, 2006; Revised July 17, 2007; Accepted August 3, 2007
Monitoring Editor: Jean Schwarzbauer

The control of gene expression by the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK) requires its translocation into the nucleus. In Drosophila S2 cells nuclear accumulation of diphospho-ERK (dpERK) is greatly reduced by interfering double-stranded RNA against Drosophila importin-7 (DIM-7) or by the expression of integrin mutants, either during active cell spreading or after stimulation by insulin. In both cases, total ERK phosphorylation (on Westerns) is not significantly affected, and ERK accumulates in a perinuclear ring. Tyrosine phosphorylation of DIM-7 is reduced in cells expressing integrin mutants, indicating a mechanistic link between these components. DIM-7 and integrins localize to the same actin-containing peripheral regions in spreading cells, but DIM-7 is not concentrated in paxillin-positive focal contacts or stable focal adhesions. The Corkscrew (SHP-2) tyrosine phosphatase binds DIM-7, and Corkscrew is required for the cortical localization of DIM-7. These data suggest a model in which ERK phosphorylation must be spatially coupled to integrin-mediated DIM-7 activation to make a complex that can be imported efficiently. Moreover, dpERK nuclear import can be restored in DIM-7–deficient cells by Xenopus Importin-7, demonstrating that ERK import is an evolutionarily conserved function of this protein.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Present addresses: M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030;

Department of Genetics, Drosophila RNAi Screening Center, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115.

Address correspondence to: Danny L. Brower (dbrower{at}email.arizona.edu)