Cdc42p-interacting protein Bem4p regulates the filamentous-growth mitogen-activated protein kinase pathway

Significance Statement

Small GTPases like the polarity establishment regulator Cdc42p can function in different settings to control cell polarity and signal transduction pathways. How Cdc42p and other proteins function in pathway-specific contexts is not clear. We show that the Cdc42p-interacting protein Bem4p regulates the MAPK pathway that controls filamentous growth in yeast. Bem4p controlled the filamentous growth pathway but not other MAPK pathways (mating or HOG) that also require Cdc42p and other shared components. Bem4p interacted with several proteins that regulate the filamentous growth pathway, including the major activator of Cdc42p, the guanine nucleotide exchange factor (GEF) Cdc24p. Bem4p interacted with the pleckstrin homology (PH) domain of Cdc24p, which functions in an auto-inhibitory capacity. Thus, Bem4p may promote activation of the major GEF for Cdc42p. Bem4p also interacts with Cdc42p and may directly promote GEF-dependent activation of Cdc42p. The association of Bem4p with other regulators of the filamentous growth pathway may lead to a pathway-specific response.

Figure legend: A possible mechanism for how Bem4p regulates Cdc42p. Bem4p is activated by signals emanating from the transmembrane regulators Msb2p and Sho1p. Bem4p binds to the PH domain of Cdc24p, which may facilitate GEF activity. Bem4p also binds to Cdc42p, which may facilitate GEF-dependent activation of the GTPase.

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Journal Reference

Pitoniak A1, Chavel CA1, Chow J1, Smith J1, Camara D1, Karunanithi S1, Li B1, Wolfe KH2, Cullen PJ3. Mol Cell Biol. 2015 ;35(2):417-36.

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1Department of Biological Sciences, SUNY-Buffalo, Buffalo, New York, USA.

2Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.

3Department of Biological Sciences, SUNY-Buffalo, Buffalo, New York, USA [email protected]

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Abstract

The ubiquitous Rho (Ras homology) GTPase Cdc42p can function in different settings to regulate cell polarity and cellular signaling. How Cdc42p and other proteins are directed to function in a particular context remains unclear. We show that the Cdc42p-interacting protein Bem4p regulates the mitogen-activated protein kinase (MAPK) pathway that controls filamentous growth in Saccharomyces cerevisiae. Bem4p controlled the filamentous-growth pathway but not other MAPK pathways (mating or high-osmolarity glycerol response [HOG]) that also require Cdc42p and other shared components. Bem4p associated with the plasma membrane (PM) protein, Sho1p, to regulate MAPK activity and cell polarization under nutrient-limiting conditions that favor filamentous growth. Bem4p also interacted with the major activator of Cdc42p, the guanine nucleotide exchange factor (GEF) Cdc24p, which we show also regulates the filamentous-growth pathway. Bem4p interacted with the pleckstrin homology (PH) domain of Cdc24p, which functions in an autoinhibitory capacity, and was required, along with other pathway regulators, to maintain Cdc24p at polarized sites during filamentous growth. Bem4p also interacted with the MAPK kinase kinase (MAPKKK) Ste11p. Thus, Bem4p is a new regulator of the filamentous-growth MAPK pathway and binds to general proteins, like Cdc42p and Ste11p, to promote a pathway-specific response.

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