CDC-42 Interactions with Par Proteins Are Critical for Proper Patterning in Polarization.

Sungrim Seirin-Lee,Eamonn A Gaffney,Adriana T Dawes

doi:10.3390/cells9092036

Sungrim Seirin-Lee, Eamonn A Gaffney + Show 1 more

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https://doi.org/10.3390/cells9092036

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Abstract

Many cells rearrange proteins and other components into spatially distinct domains in a process called polarization. This asymmetric patterning is required for a number of biological processes including asymmetric division, cell migration, and embryonic development. Proteins involved in polarization are highly conserved and include members of the Par and Rho protein families. Despite the importance of these proteins in polarization, it is not yet known how they interact and regulate each other to produce the protein localization patterns associated with polarization. In this study, we develop and analyse a biologically based mathematical model of polarization that incorporates interactions between Par and Rho proteins that are consistent with experimental observations of CDC-42. Using minimal network and eFAST sensitivity analyses, we demonstrate that CDC-42 is predicted to reinforce maintenance of anterior PAR protein polarity which in turn feedbacks to maintain CDC-42 polarization, as well as supporting posterior PAR protein polarization maintenance. The mechanisms for polarity maintenance identified by these methods are not sufficient for the generation of polarization in the absence of cortical flow. Additional inhibitory interactions mediated by the posterior Par proteins are predicted to play a role in the generation of Par protein polarity. More generally, these results provide new insights into the role of CDC-42 in polarization and the mutual regulation of key polarity determinants, in addition to providing a foundation for further investigations.

Highlights

Intracellular polarization, whereby a cell establishes a pattern and specifies a spatial axis by segregating proteins and other factors to distinct domains, is a fundamental and ubiquitous process.Polarization is implicated in a wide variety of biological phenomena including asymmetric cell division, cell migration, wound healing, and embryonic development [1,2,3]
We develop a continuum model of Par and Rho protein dynamics in the generation and maintenance of polarization in the early C. elegans embryo from the rational simplification for the underlying interactions among CDC-42 and the PAR proteins that have been uncovered by numerous experimental studies
We found that the magnitude of the sensitivity indices for Si and STi are substantially different for the pPAR and CDC-42 cases, but not for the anterior Par proteins (aPAR) case, suggesting that maintenance of pPAR and CDC-42 polarity are more strongly affected by interactions with the other proteins in the network, but maintenance of aPAR polarity operates largely independently of the other proteins

Summary

Introduction

Intracellular polarization, whereby a cell establishes a pattern and specifies a spatial axis by segregating proteins and other factors to distinct domains, is a fundamental and ubiquitous process.Polarization is implicated in a wide variety of biological phenomena including asymmetric cell division, cell migration, wound healing, and embryonic development [1,2,3]. Intracellular polarization, whereby a cell establishes a pattern and specifies a spatial axis by segregating proteins and other factors to distinct domains, is a fundamental and ubiquitous process. Aberrant polarization is thought to play a role in disease progression: a hallmark of the epithelial to mesenchymal transition (EMT) in malignant cells is the acquisition of a polarized migratory phenotype [4,5]. The same key polarity determinants, including the Par and Rho protein families, are required for forming the pattern associated with polarization in virtually all cell types and organisms [3]. Despite the importance of polarization and the highly conserved nature of the proteins involved, the mechanisms and signalling networks regulating this patterning process are not completely understood. Two main protein families have been intensively studied for their role in polarization: Rho proteins and Par proteins (Figure 1). Referred to as Rho GTPases, are monomeric G proteins

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