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Sho1: How to Convert Pressure into a Mating Response

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Science's STKE  29 Jun 2004:
Vol. 2004, Issue 239, pp. tw228-TW228
DOI: 10.1126/scisignal.2392004tw228

Although we think of cell signaling in terms of linear cascades, signal transduction pathways interact with one another to form a complex network that governs cell behavior. The mechanisms whereby information is channeled into one pathway over another with which it shares signaling components, however, remain incompletely understood. Two groups used mutational analysis of a yeast mitogen-activated protein kinase (MAPK) pathway sensitive to high osmolarity, which contains the MAPK kinase kinase (MAPKKK) Ste11 in common with a distinct MAPK signaling pathway involved in mating, to investigate mechanisms governing information flow and pathway specificity. The osmosensor Sho1 activates Ste11, which activates the MAPKK Pbs2, which activates the MAPK Hog1, which translocates to the nucleus to activate target genes. Pbs2 also acts as scaffold for Sho1, Ste11, and Hog1; in its absence, high osmolarity activates the mating pathway through Sho1 stimulation of Ste11. Marles et al. created Sho1 SH3 domain mutants with different binding affinities for Pbs2 and found that increased activation of the Sho1 osmosensing pathway directly correlated with increasing affinity for Pbs2, whereas decreasing affinity correlated with crosstalk to the mating pathway. Not only the binding affinity of the SH3 domain, but also the specific sequence of this domain are important for pathway selectivity. Sho1 constructs containing a mutant Fyn SH3 domain that bound Pbs2 with high affinity were ineffective at activating the osmosensing pathway. Furthermore, Sho1 SH3 mutants that did not affect Pbs2 binding interfered with crosstalk. Thus, binding affinity for the appropriate target is an important determinant of pathway choice but not the only one. Wondering how the Sho1 and Ste11 interaction persists in the absence of Pbs2, Zarrinpar et al. showed that the effects of specific Sho1 mutations on osmoresistance and mating crosstalk were distinct. Mutations of the SH3 domain that destroyed osmoresistance permitted crosstalk, whereas mutation of a distinct region in the C terminus that bound Ste11 directly abolished crosstalk with little effect on osmoresistance. In yeast expressing constitutively active Ste11, which activates the mating response, Sho1 was required for osmoresistance. Thus, Sho1, as well as Pbs2, appears to serve a scaffolding function, and a coordinated network of interactions involving two coscaffolding proteins appears to determine functionality of the Sho1 osmosensing pathway.

J. A. Marles, S. Dahesh, J. Haynes, B. J. Andrews, A. R. Davidson, Protein-protein interaction affinity plays a crucial role in controlling the Sho1p-mediated signal transduction pathway in yeast. Mol. Cell 14, 813-823 (2004). [Online Journal]

A. Zarrinpar, R. P. Bhattacharyya, M. P. Nittler, W. A. Lim, Sho1 and Pbs2 act as coscaffolds linking components in the yeast high osmolarity MAP kinase pathway. Mol. Cell 14, 825-832 (2004). [Online Journal]

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