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MBC in Press, published online ahead of print February 21, 2003
Mol. Biol. Cell 10.1091/mbc.E02-10-0699

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Submitted on October 30, 2002
Revised on January 21, 2003
Accepted on February 5, 2003

Nuclear export and plasma membrane recruitment of the Ste5 scaffold are coordinated with oligomerization and association with signal transduction components

Yunmei Wang1 and Elaine A. Elion1*

1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 240 Longwood Avenue, Boston, MA 02115

* Corresponding author. E-mail address: elaine_elion{at}hms.harvard.edu.

The Ste5 scaffold activates an associated mitogen-activated protein kinase (MAPK) cascade by binding through its RING-H2 domain to a G{beta}{gamma} dimer (Ste4/Ste18) at the plasma membrane in a recruitment event that requires prior nuclear shuttling of Ste5. Genetic evidence suggests that Ste5 must oligomerize to function, but its impact on Ste5 function and localization is unknown. Here, we show that oligomerization affects Ste5 activity and localization. The vast majority of Ste5 is monomeric, suggesting that oligomerization is tightly regulated. Increasing the pool of Ste5 oligomers increases association with Ste11. Remarkably, Ste5 oligomers are also more efficiently exported from the nucleus, retained in the cytoplasm by Ste11 and better recruited to the plasma membrane, resulting in constitutive activation of the mating MAPK cascade. Co-precipitation tests show that the RING-H2 domain is the key determinant of oligomerization. Mutational analysis suggests that the leucine-rich domain limits the accessibility of the RING-H2 domain and inhibits export and recruitment in addition to promoting Ste11 association and activation. Our results suggest that the major form of Ste5 is an inactive monomer with an inaccessible RING-H2 domain and Ste11 binding site, whereas the active form is an oligomer that is more efficiently exported and recruited and has a more accessible RING-H2 domain and Ste11 binding site.




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