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PNAS 96 (23): 13259-13263

Copyright © 1999 by the National Academy of Sciences.


Functional analysis of CNK in RAS signaling

Marc Therrien*, Allan M. Wong, Elaine Kwan, and Gerald M. Rubin{dagger}

Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200

Contributed by Gerald M. Rubin

Accepted for publication September 16, 1999.

Abstract: Connector enhancer of KSR (CNK) is a multidomain protein required for RAS signaling. Its C-terminal portion (CNKC-term) directly binds to RAF. Herein, we show that the N-terminal portion of CNK (CNKN-term) strongly cooperates with RAS, whereas CNKC-term efficiently blocks RAS- and RAF-dependent signaling when overexpressed in the Drosophila eye. Two effector loop mutants of RASV12, S35 and C40, which selectively activate the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase pathways, respectively, do not cooperate with CNK. However, a strong cooperation is observed between CNK and RASV12G37, an effector loop mutant known in mammals to activate specifically the RAL pathway. We have identified two domains in CNKN-term that are critical for cooperation with RAS. Our results suggest that CNK functions in more than one pathway downstream of RAS. CNKc-term seems to regulate RAF, a component of the MAPK pathway, whereas CNKN-term seems to be involved in a MAPK-independent pathway.

Key Words: RAF

* Present address: Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, PQ, Canada H2W 1R7.

{dagger} To whom reprint requests should be addressed. E-mail: gerry{at}

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