In an interdisciplinary collaboration between two research groups at the IMSB and the IFNH, the impact of cell surface proteins on adipocyte function was characterized.
The molecular cause for dysfunctional adipocyte behavior related to obesity and the development of type 2 diabetes are poorly characterized. ETH researchers subjected cell surface proteins to contribute to the malfunction of adipocytes in obesity. The relative comparison of the surfaceome maps of adipocytes between various mouse models of metabolic disorders revealed modulated location-specific abundance levels. In further experiments it was demonstrated that a subset of the cell surface proteins possessing modulated abundance levels influence adipocyte function. Targeting the activity of the identified cell surface proteins could be an interesting approach to reverse the dysfunctional phenotype of adipocytes in obesity.
Full Reference: Moest H, Frei AP, Bhattacharya I, Geiger M, Wollscheid B, Wolfrum C. Malfunctioning of adipocytes in obesity is linked to quantitative surfaceome changes. Biochim Biophys Acta. 2013 Apr 10. pii: S1388-1981(13)00086-3. doi: 10.1016/j.bbalip.2013.04.001
The phosphatase and tensin homolog (PTEN) tumor suppressor gene is deregulated in many
advanced prostate cancers, leading to activation of the PI3K signaling pathway and thus in-
creased cell survival.
The objective of the Phase II trial of single-agent everolimus (Afinitor®, made by Novartis Phar-
maceuticals Corporation) in chemotherapy-naive patients with castration-resistant prostate can-
cer was to evaluate everolimus, an inhibitor of mTOR, in patients with metastatic castration-
resistant prostate cancer (mCRPC), and to explore potentially predictive serum biomarkers by
In the study, the concentration of ProteoMediX’ PI3K pathway sensitive biomarkers was meas-
ured in blood of 28 chemotherapy-naive patients with mCRPC and progressive disease. 13 pa-
tients thereof reached the primary endpoint which was progression-free survival (PFS) at
12 weeks. Interestingly, higher serum levels of several of ProteoMediX’ proprietary biomarkers
were predictive for reaching the primary endpoint.
As a conclusion of this study the trial chairperson Arnoud Templeton, M.D., states: ”Everolimus
activity in unselected patients with mCRPC is moderate, but PTEN deletion could be predictive
for response.” Several protein biomarkers were able to predict PFS at 12 weeks. These results
may represent one step forward in the direction of creating target-driven subgroups in CRPC
that may derive benefit from a specific treatment. Prospective validation of these potential bio-
markers is warranted.
Dr. Ralph Schiess, CEO and co-founder commented: “Publication of these exciting results in the
high impact journal European Urology underscores the importance of the data. We are confident
that we can further validate our biomarkers for the use of patient stratification.”
Full Reference: Templeton AJ, Dutoit V, Cathomas R, Rothermundt C, Bärtschi D, Dröge C, Gautschi O, Borner M, Fechter E, Stenner F, Winterhalder R, Müller B, Schiess R, Wild PJ, Rüschoff JH, Thalmann G, Dietrich PY, Aebersold R, Klingbiel D, Gillessen S; on behalf of the Swiss Group for Clinical Cancer Research (SAKK). Phase 2 Trial of Single-agent Everolimus in Chemotherapy-naive Patients with Castration-resistant Prostate Cancer (SAKK 08/08). Eur Urol. 2013 Apr 6. pii: S0302-2838(13)00294-7. doi: 10.1016/j.eururo.2013.03.040
A new study by researches from the Aebersold and Stoffel research groups provides a detailed and global map of specific and common BACE1/2 substrates in pancreatic β-cells and offers molecular insights of how these proteases regulate β-cell growth and function.
Expansion of functional islet β-cell mass is a physiological process to compensate for increased insulin demand. Deficiency or pharmacological inhibition of the plasma membrane protease BACE2 enhances pancreatic β-cell function and proliferation, and therefore BACE2 is a putative target for the therapeutic intervention under conditions of β-cell loss and dysfunction. To gain a molecular understanding of BACE2 function, we performed a systematic and quantitative proteomic analysis to map the natural substrate repertoire of BACE2 and its homologue BACE1 in β-cells. Loss- and gain-of-function studies of in vitro and in vivo models identified specific and functionally heterogeneous targets. Our analysis revealed non-redundant roles of BACE1/2 in ectodomain shedding with BACE1 regulating a broader and BACE2 a more distinct set of β-cell-enriched substrates including two proteins of the seizure 6 protein family (SEZ6L and SEZ6L2). Lastly, our study provides insights into the global β-cell sheddome and secretome, an important prerequisite to uncover novel mechanisms contributing to β-cell homeostasis and a resource for therapeutic target and biomarker discoveries.
Full Reference: Stützer I, Selevsek N, Esterházy D, Schmidt A, Aebersold R, Stoffel M. Systematic Proteomic Analysis Identifies β-Site Amyloid Precursor Protein Cleaving Enzyme 2 and 1 (BACE2 and BACE1) Substrates in Pancreatic β-Cells. J Biol Chem. 2013 Apr 12;288(15):10536-47. doi: 10.1074/jbc.M112.444703.
Alternative approaches to analyze the structure of protein complexes by the use of mass spectrometry are described by IMSB researchers from the Aebersold group.
In this review IMSB researchers from the Aebersold group describe how the structure of protein complexes can be investigated using mass spectrometry (MS). Focus is laid on recent developments in chemical-cross-linking MS (CX-MS) and native MS and their application to challenging problems in structural biology.
Full Reference: Walzthoeni T, Leitner A, Stengel F, Aebersold R. Mass spectrometry supported determination of protein complex structure. Curr Opin Struct Biol. 2013 Mar 19. pii: S0959-440X(13)00037-7. doi: 10.1016/j.sbi.2013.02.008
Full Reference: Gstaiger M, Aebersold R. Genotype-phenotype relationships in light of a modular protein interaction landscape.
Mol Biosyst. 2013 Mar 26. doi: 10.1039/C3MB25583B
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