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12. Geriatric pre-surgical optimization in the NCORP (Alliance).

Author

Finlayson, Emily, primary, Gunn, Heather, additional, Barber, Anne, additional, Lowenstein, Lisa M., additional, Dohan, Daniel Paul, additional, Broering, Jeanette M., additional, Dockter, Travis, additional, Tan, Angelina D., additional, Dueck, Amylou C., additional, Bailey, Lisa, additional, Chow, Selina Lai-ming, additional, Wills, Rachel, additional, Jatoi, Aminah, additional, Lee, Eugene K., additional, Delacroix, Scott Edward, additional, Gills, Jessie, additional, Mulligan, Charles, additional, Hayseen, Therese, additional, and Chang, George J., additional

Published
2023
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15. A Novel Homeostatic Mechanism Tunes PI(4,5)P2-dependent Signaling at the Plasma Membrane

Author

Wills, Rachel Christine and Wills, Rachel Christine

Abstract

The lipid molecule phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) controls virtually all aspects of plasma membrane (PM) function in animal cells. These functions range from cellular signaling to selective membrane permeability to the attachment of the cytoskeleton. Upon the reduction of PI(4,5)P2 these cellular functions are dysregulated. The majority of PI(4,5)P2 is synthesized by type 1 phosphatidylinositol 4-phosphate 5-kinase (PIP5K). However, the mechanism by which PIP5K localizes to the PM to access its substrate phosphoinositide 4-phosphate (PI4P) is not well known. Therefore, understanding the regulation of this kinase is critical for determining how the cell maintains PI(4,5)P2 homeostasis. We observed PM localization of over-expressed PIP5K isoforms and endogenously tagged PIP5K1A to determine the potential mechanisms for PM association. After experimentally altering the phosphoinositide composition of the PM, we were able to observe the acute corresponding changes in PIP5K localization. PIP5K remained localized with the PM in the presence of PI4P and PI(4,5)P2. Furthermore, we determined that two basic residues in the C-terminal tail are necessary for this PM interaction. The crystal structure of PIP5K displays these two residues opposite the activation loop and near an unstructured insert loop. Ultimately, we believe that the insert loop functions as a PI(4,5)P2 binding pocket or confers allosteric regulation to reveal a cryptic PI(4,5)P2 binding site on PIP5K to facilitate its PM localization. On the other hand, increased levels of PI(4,5)P2 are also associated with a wide range of diseases. Yet, it remains unclear how cells sense and maintain PI(4,5)P2 levels without exceeding the basal level. Here, we show that the type 2 phosphatidylinositol 5-phosphate 4-kinase (PIP4K) family of enzymes, that synthesize PI(4,5)P2 via a minor pathway, also function as sensors of tonic PI(4,5)P2 levels. We show that PIP4K inhibits the synthesis of PI(4,5)P2 and

Published
2023

19. Improving Patient-Centered Communication in Breast Cancer: A Study Protocol for a Multilevel Intervention of a Shared Treatment Deliberation System (SharES) within the NCI Community Oncology Research Program (NCORP) (Alliance A231901CD)

Author

Hawley, Sarah, primary, Kidwell, Kelley, additional, Zahrieh, David, additional, Barber, Anne, additional, Wills, Rachel, additional, Rankin, Aaron, additional, Chow, Selina, additional, Hofer, Timothy, additional, Jagsi, Reshma, additional, and Neuman, Heather, additional

Published
2022
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20. Additional file 2 of Improving patient-centered communication in breast cancer: a study protocol for a multilevel intervention of a shared treatment deliberation system (SharES) within the NCI community oncology research program (NCORP) (Alliance A231901CD)

Author

Hawley, Sarah T., Kidwell, Kelley, Zahrieh, David, McCarthy, Anne, Wills, Rachel, Rankin, Aaron, Hofer, Timothy, Chow, Selina, Jagsi, Reshma, and Neuman, Heather

Abstract

Additional file 2. Model informed consent for clinicians.

Published
2023
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21. Additional file 1 of Improving patient-centered communication in breast cancer: a study protocol for a multilevel intervention of a shared treatment deliberation system (SharES) within the NCI community oncology research program (NCORP) (Alliance A231901CD)

Author

Hawley, Sarah T., Kidwell, Kelley, Zahrieh, David, McCarthy, Anne, Wills, Rachel, Rankin, Aaron, Hofer, Timothy, Chow, Selina, Jagsi, Reshma, and Neuman, Heather

Abstract

Additional file 1. Model consent form for patients.

Published
2023
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25. Increasing socioeconomically disadvantaged patients’ engagement in breast cancer surgery decision-making through a shared decision-making intervention (A231701CD): protocol for a cluster randomised clinical trial

Author

Schumacher, Jessica R, primary, Zahrieh, David, additional, Chow, Selina, additional, Taylor, John, additional, Wills, Rachel, additional, Hanlon, Bret M, additional, Rathouz, Paul J, additional, Tucholka, Jennifer L, additional, and Neuman, Heather B, additional

Published
2022
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26. A novel homeostatic mechanism tunes PI(4,5)P2-dependent signaling at the plasma membrane.

Author

Wills, Rachel C., Doyle, Colleen P., Zewe, James P., Pacheco, Jonathan, Hansen, Scott D., and Hammond, Gerald R. V.

Subjects
*CELL membranes, *CELL physiology, *HOMEOSTASIS, *PERMEABILITY, *CYTOSKELETON
Abstract

The lipid molecule phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] controls all aspects of plasma membrane (PM) function in animal cells, from its selective permeability to the attachment of the cytoskeleton. Although disruption of PI(4,5)P2 is associated with a wide range of diseases, it remains unclear how cells sense and maintain PI(4,5)P2 levels to support various cell functions. Here, we show that the PIP4K family of enzymes, which synthesize PI(4,5)P2 via a minor pathway, also function as sensors of tonic PI(4,5)P2 levels. PIP4Ks are recruited to the PM by elevated PI(4,5)P2 levels, where they inhibit the major PI(4,5)P2-synthesizing PIP5Ks. Perturbation of this simple homeostatic mechanism reveals differential sensitivity of PI(4,5)P2-dependent signaling to elevated PI(4,5)P2 levels. These findings reveal that a subset of PI(4,5)P2-driven functions might drive disease associated with disrupted PI(4,5)P2 homeostasis. [ABSTRACT FROM AUTHOR]

Published
2023
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35. PI(4,5)P2: signaling the plasma membrane.

Author

Wills, Rachel C. and Hammond, Gerald R. V.

Subjects
*CELL membranes, *ION channels, *CELL polarity, *TRAFFIC engineering, *CYTOSKELETON
Abstract

In the almost 70 years since the first hints of its existence, the phosphoinositide, phos)phatidyl-D-myo-inositol 4,5-bisphosphate has been found to be central in the biological regulation of plasma membrane (PM) function. Here, we provide an overview of the sig)naling, transport and structural roles the lipid plays at the cell surface in animal cells. These include being substrate for second messenger generation, direct modulation of receptors, control of membrane traffic, regulation of ion channels and transporters, and modulation of the cytoskeleton and cell polarity. We conclude by re-evaluating PI(4,5)P2’s designation as a signaling molecule, instead proposing a cofactor role, enabling PM-selective function for many proteins. [ABSTRACT FROM AUTHOR]

Published
2022
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45. Serum Autotaxin/ENPP2 Correlates with Insulin Resistance in Older Humans with Obesity

Author

Reeves, Valerie L., Trybula, Joy S., Wills, Rachel C., Goodpaster, Bret H., Dubé, John J., Kienesberger, Petra C., and Kershaw, Erin E.

Subjects
Blood Glucose, Male, obesity, Aging, Phosphoric Diester Hydrolases, Middle Aged, Article, metabolic syndrome, Weight Reduction Programs, Autotaxin, insulin resistance, Animals, Humans, Female, adipokines, lysophosphatidic acid, Adiposity, Aged
Abstract

Objective Autotaxin (ATX) is an adipocyte-derived lysophospholipase D that generates the lipid signaling molecule lysophosphatidic acid (LPA). The ATX/LPA pathway in adipose tissue has recently been implicated in obesity and insulin resistance in animal models, but the role of circulating ATX in humans remains unclear. The aim of the present study was to determine the relationship between serum ATX and insulin resistance. Methods In this retrospective study, older (60–75 years), non-diabetic human participants with overweight or obesity (BMI 25–37 kg/m2), were characterized for metabolic phenotype including measures of energy, glucose, and lipid homeostasis. The relationship between serum ATX and metabolic parameters was then determined using correlative and predictive statistics. Results Serum ATX was higher in females than in males. After controlling for sex, serum ATX correlated with multiple measures of adiposity and glucose homeostasis/insulin action. Serum ATX and BMI also independently predicted glucose infusion rate during a hyperinsulinemic euglycemic clamp and homeostatic model assessment of insulin resistance after controlling for sex and medication use. Conclusion Serum ATX correlates with and predicts measures of glucose homeostasis and insulin sensitivity in older humans, suggesting that it may be a potential pathogenic factor and/or diagnostic/therapeutic target for insulin resistance in this population.

Published
2015

47. Peptide Cyclization at High Concentration.

Author

Wills, Rachel D., Adebomi, Victor T., and Raj, Monika

Subjects
*CYCLIC peptides, *AMINO acids, *PEPTIDES, *MACROCYCLIC compounds, *CHEMISTRY
Abstract

The emergence of cyclic peptides as pharmaceuticals has led to an eruption of new methodologies for macrocyclization. However, the cyclization of peptides at high concentrations presents a challenge due to the production of side products like dimers and oligomers. This factor is more pronounced with the cyclization of peptides composed of fewer than seven amino acids, thus has created a need for a new synthetic strategy. Herein, we will elucidate a new chemoselective method termed 'CyClick' that works in an exclusively intramolecular fashion preventing the formation of commonly occurring side products such as dimers and oligomers, even at relatively high concentration. 1 Introduction 2 Known Methodologies 3 Novel CyClick Chemistry 4 Conclusion and Outlook [ABSTRACT FROM AUTHOR]

Published
2020
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