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Exploring the interplay between protein conformational changes and phosphorylation in a pancreatic cancer cell and stellate cell co-culture system

ABSTRACT: A global exploration of the complex interplay between protein conformational changes and phosphorylation events in cell-cell interactions is crucial for understanding the dynamic nature of protein modifications. This understanding is essential for developing novel targeted therapies for pancreatic cancer, particularly in the context of interactions between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs). However, protein conformational changes that occur during PCCs-PSCs interactions remain poorly studied, and the relationship between these changes and phosphorylation is not well understood. Here, we present a comprehensive mass spectrometry-based study investigating the interplay between protein conformational alterations and phosphorylation in a co-culture system of pancreatic ductal adenocarcinoma cells (PANC-1) and PSCs. Our results demonstrate that 435 proteins exhibiting conformational changes were detected during the co-culture of PANC-1 with PSCs, primarily involving proteins associated with the tricarboxylic acid (TCA) cycle, glycolysis/gluconeogenesis, and carbon metabolism. Our findings also highlight a potential association between phosphorylation and protein conformational changes. Moreover, we identified five potential conformational targets, including ACLY, ACO1, ACO2, IDH1, and OGDH, which may provide valuable insights into the molecular pathways underlying gemcitabine resistance in pancreatic cancer. Overall, these results offer novel insights into protein conformational changes and their potential link to phosphorylation in the context of cancer-stromal cell interactions, paving the way for structure-based, targeted therapeutic strategies for pancreatic cancer treatment.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pancreatic Stellate Cell

DISEASE(S): Pancreatic Cancer

SUBMITTER: Haiyan Lu

LAB HEAD: Lingjun Li

PROVIDER: PXD059270 | Pride | 2025-12-15

REPOSITORIES: Pride

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Project description:Large-scale studies of protein phosphorylation have generally focused on determining the sites and stoichiometry of phosphorylated proteins derived from different biological specimens such as cell lines and tissue samples. While such information is important for understanding the role of phosphorylation in biological systems, it fails to expose the relationship between protein phosphorylation and protein function. Because of the close link between protein function and protein folding stability, knowledge about phosphorylation-induced protein folding stability changes can lead to a better understanding of the functional effects of protein phosphorylation. As part of this work, the Stability of Proteins from Rate of OXidation (SPROX) and Limited Proteolysis (LiP) techniques were utilized to identify phosphorylation-induced conformational and stability changes in proteins derived from a human breast cancer cell line MCF-7. This was accomplished by comparing the conformation properties of proteins in two MCF-7 cell lysates including one that was and one that was not dephosphorylated with alkaline phosphatase. The SPROX technique, which probes the global unfolding/refolding properties of proteins, identified 168 proteins with phosphorylation-induced stability changes, and the LiPs technique, which probes the more local unfolding/refolding properties of proteins, identified 251 proteins with phosphorylation-induced stability changes. A total of 49 proteins identified here with phosphorylation-induced conformational changes, were previously identified in phosphoproteomic studies to be differentially phosphorlyated in different human breast cancer subtypes. A total of 98 proteins identified here overlapped with protein hits previously found to be differentially stabilized in four human breast cancer phenotypes, suggesting that the phosphorylated changes observed here may be disease related. The experimental approach and results reported here create a novel perspective in understanding large-scale molecular influence of phosphorylation and a shortcut in finding possible functionally significant PTMs in cellular proteins.

Project description:Large-scale studies of protein phosphorylation have generally focused on determining the sites and stoichiometry of phosphorylated proteins derived from different biological specimens such as cell lines and tissue samples. While such information is important for understanding the role of phosphorylation in biological systems, it fails to expose the relationship between protein phosphorylation and protein function. Because of the close link between protein function and protein folding stability, knowledge about phosphorylation-induced protein folding stability changes can lead to a better understanding of the functional effects of protein phosphorylation. As part of this work, the Stability of Proteins from Rate of OXidation (SPROX) and Limited Proteolysis (LiP) techniques were utilized to identify phosphorylation-induced conformational and stability changes in proteins derived from a human breast cancer cell line MCF-7. This was accomplished by comparing the conformation properties of proteins in two MCF-7 cell lysates including one that was and one that was not dephosphorylated with alkaline phosphatase. The SPROX technique, which probes the global unfolding/refolding properties of proteins, identified 168 proteins with dephosphorylation-induced stability changes, and the LiPs technique, which probes the more local unfolding/refolding properties of proteins, identified 251 proteins with dephosphorylation-induced stability changes. A total of 49 proteins identified here with dephosphorylation-induced conformational changes, were previously identified in phosphoproteomic studies to be differentially phosphorlyated in different human breast cancer subtypes. A total of 98 proteins identified here overlapped with protein hits previously found to be differentially stabilized in four human breast cancer phenotypes, suggesting that the phosphorylated changes observed here may be disease related. The experimental approach and results reported here create a novel approach for identifying functionally significant PTMs in proteins.

			Action	DRS
	C02_P_01.raw	Raw
	CO1_P_01.raw	Raw
	CO1_P_02.raw	Raw
	CO1_T_01.raw	Raw
	CO1_T_02.raw	Raw

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Exploring the interplay between protein conformational changes and phosphorylation in a pancreatic cancer cell and stellate cell co-culture system

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