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Molecular and Cellular Biology, July 2000, p. 4736-4744, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Ste20 Kinase Misshapen Regulates Both Photoreceptor Axon Targeting and Dorsal Closure, Acting Downstream of Distinct Signals

Yi-Chi Su,1 Corinne Maurel-Zaffran,2 Jessica E. Treisman,2,* and Edward Y. Skolnik1,*

Department of Pharmacology1 and Department of Cell Biology,2 Skirball Institute of Biomolecular Medicine, New York University Medical Center, New York, New York

Received 29 November 1999/Returned for modification 20 February 2000/Accepted 27 March 2000

We have previously shown that the Ste20 kinase encoded by misshapen (msn) functions upstream of the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase module in Drosophila. msn is required to activate the Drosophila JNK, Basket (Bsk), to promote dorsal closure of the embryo. A mammalian homolog of Msn, Nck interacting kinase, interacts with the SH3 domains of the SH2-SH3 adapter protein Nck. We now show that Msn likewise interacts with Dreadlocks (Dock), the Drosophila homolog of Nck. dock is required for the correct targeting of photoreceptor axons. We have performed a structure-function analysis of Msn in vivo in Drosophila in order to elucidate the mechanism whereby Msn regulates JNK and to determine whether msn, like dock, is required for the correct targeting of photoreceptor axons. We show that Msn requires both a functional kinase and a C-terminal regulatory domain to activate JNK in vivo in Drosophila. A mutation in a PXXP motif on Msn that prevents it from binding to the SH3 domains of Dock does not affect its ability to rescue the dorsal closure defect in msn embryos, suggesting that Dock is not an upstream regulator of msn in dorsal closure. Larvae with only this mutated form of Msn show a marked disruption in photoreceptor axon targeting, implicating an SH3 domain protein in this process; however, an activated form of Msn is not sufficient to rescue the dock mutant phenotype. Mosaic analysis reveals that msn expression is required in photoreceptors in order for their axons to project correctly. The data presented here genetically link msn to two distinct biological events, dorsal closure and photoreceptor axon pathfinding, and thus provide the first evidence that Ste20 kinases of the germinal center kinase family play a role in axonal pathfinding. The ability of Msn to interact with distinct classes of adapter molecules in dorsal closure and photoreceptor axon pathfinding may provide the flexibility that allows it to link to distinct upstream signaling systems.

* Corresponding author. Mailing address for Edward Skolnik: New York University Medical Center, Department of Pharmacology, Skirball Institute of Biomolecular Medicine, 540 First Ave., New York, NY 10016. Phone: (212) 263-7458. Fax: (212) 263-5711. E-mail: Skolnik{at}saturn.med.nyu.edu. Mailing address for Jessica Treisman: New York University Medical Center, Department of Cell Biology, Skirball Institute of Biomolecular Medicine, 540 First Ave., New York, NY 10016. Phone: (212) 263-1031. Fax: (212) 263-7760. E-mail: Treisman{at}saturn.med.nyu.edu.

Molecular and Cellular Biology, July 2000, p. 4736-4744, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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