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Our lab is interested in understanding how signal transduction pathways regulate morphogenetic responses. We study MAP kinase pathways in fungal species including the model genetic system budding yeast and human pathogen C. albicans. One focus of the lab is to understand how the polarity Rho-type GTPase Cdc42 is activated in the context of a specific MAP kinase pathway. Cdc42 and other proteins can function in multiple pathways. This is part of a general problem surrounding signaling pathways that control specific processes through networks of common or shared factors. How a specific output results from the activation of a common module is not clear and is a problem addressed by our lab. Understanding ‘signaling specificity’ is relevant to human health because cross talk between pathways can lead to cancer and other diseases. 

Filamentous growth is a developmental change that many fungal species undergo in response to nutrient limitation and other stresses. Our lab and other labs have begun to define the proteins that regulate Cdc42 and MAP kinase pathways during filamentous growth.

Budding yeast change their shape, polarity, and adhesive properties when grown in nutrient-limited media. This response is regulated by signaling pathways including a Cdc42-dependent MAP kinase pathway. We use this change to understand the role signaling pathways play in regulating eukaryotic differentiation. Colonies of yeast (S.cerevisiae) in certain genetic backgrounds also produce a ruffled morphology (right). The colony morphology results from adhesive contacts between cells and also requires the action of signaling pathways.

One of the proteins that regulates Cdc42 during filamentous growth is a cell-surface glycoprotein of the mucin family. Mucins are sticky glycoproteins in eukaryotes that in some instances can also regulate cellular responses. The signaling mucin Msb2 is a transmembrane regulator of the Cdc42-dependent MAPK pathway. Msb2 functions with other cell-surface proteins to control Cdc42 and downstream factors during MAP kinase pathway regulation. Our lab has defined the activation mechanism for this protein. We found that the unfolded protein response feeds into Msb2 regulation, by governing the cleavage and activation of the protein by the aspartyl protease Yps1. Thus, a cleavage-dependent activation mechanism involves nutrient-dependent processing of the protein by a quality-control pathway.
Another protein that regulates Cdc42 is the scaffold-type adaptor Bem4. We found that Bem4 associates with many of the proteins that regulate the fMAPK pathway. Because Bem4 does not regulate other MAPK pathways in yeast that share components with fMAPK, we think that Bem4 may help direct Cdc42 to one of the many pathways in which it functions.

The Cdc42p-dependent MAP kinase pathway that regulates filamentous growth. Under nutrient-limiting conditions, Msb2 is activated by processing and release of the inhibitory extracellular domain by the protease Yps1 (Vadaie et al. 2008). Activated Msb2 and Sho1 function through Bem4, which binds to the PH domain of Cdc24 to relieve auto-inhibition. Bem4 interacts with Cdc42 and Ste11 and functions in a complex with Kss1 (dashed arrow), to regulate the filamentous growth pathway (Pitoniak et al. 2015). In green, positional marks also contribute to the regulation of the pathway through the GTPase Rsr1 (see Basu et al. 2016 for details).

We have recently identified another connection between Cdc42's role in regulating the filamentous growth MAPK pathway and positional or spatial cues in the cell. Bud-site-selection proteins, previously thought of as static marks that dictate which end the cell grows from, were found to regulate Cdc42-dependent MAP kinase signaling. This unexpected finding connects the cell's positional cues to the regulation of a differentiation-type MAP kinase pathway.
The MAPK pathway is one of many pathways that regulate filamentous growth. Multiple pathways that impact the response operate in a coordinated network. Specifically, the pathways can regulate each others' activity and each others' target genes. The identification of the network members and elucidation of the ways that different pathways work together to induce a response is an important problem that the lab and the signaling community continue to explore.
The activity of the MAPK pathway (yellow circle) is affected by other pathways that regulate filamentous growth. Each dot represents a pathway, each line, a functional connection between pathways or shared targets. See Chavel et al. 2014 for more information.
We have begun to expand our understanding of Cdc42-dependent pathways into fungal pathogens. Like in budding yeast, signaling mucins and plasma-membrane proteins regulate Cdc42-dependent MAP kinase pathways in plant and animal fungal pathogens. We are studying how Candida albicans - a major human pathogen - undergoes filamentous growth in an Msb2-dependent manner.
Cullen Lab in the Department of Biological Sciences at the State University of Buffalo
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