Arbeitsgruppe Prömel

 

Dr. Simone Prömel
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Telefon: +49 (0)341 97 22 147
Telefax: +49 (0)341 97 22 159

 

Arbeitsgruppe Prömel

 

Dr. Simone Prömel
E-Mail: Diese E-Mail-Adresse ist vor Spambots geschützt! Zur Anzeige muss JavaScript eingeschaltet sein!

Telefon: +49 (0)341 97 22 147
Telefax: +49 (0)341 97 22 159

 

Overview

All multicellular organisms are highly dependent on the capacity developed by their cells to communicate with each other and with their environment. G protein-coupled receptors (GPCRs) play a central role in controlling this communication. These seven transmembrane receptors regulate numerous physiological mechanisms in health and disease and thus, bear an immense pharmacological potential. One class of to date enigmatic GPCRs are Adhesion GPCRs (aGPCRs). Despite their essential functions in processes such as neurobiology, immunology or development and their unique architecture facilitating cell and matrix interactions, Adhesion GPCRs are by far the most poorly understood receptor class.

Our group is interested in understanding the molecular mechanisms underlying Adhesion GPCR activation and activity and how these are translated into physiological function in development or metabolic processes. How do Adhesion GPCRs function in a physiological context? Which molecular mechanisms are required? We use the roundworm Caenorhabditis elegans and the mouse as model organisms as well as various cell culture models to address these questions and to link physiological functions with molecular mechanisms.

 

Research

Molecular mechanisms of Adhesion GPCR activation/activity and their involvement in cellular processes

Adhesion GPCRs are not only functionally highly diverse receptors. They also display unique structural features that set them apart from other GPCRs. They are often described as hybrids fulfilling dual roles in adhesion and signalling. Besides a seven transmembrane domain (7TM) their characteristic features are their extraordinarily long N termini encompassing various domains associated with cell adhesion etc. Via these extracellular entities aGPCR mediate different functions: classical G protein signals but also functions solely dependent on the N terminus which are highly unusual for GPCRs. One main focus of our work is to understand how aGPCRs mediate these numerous signals and the role the extraordinarily long and complex N termini play. Using Latrophilins as prototypic members of the class in the versatile model organism C. elegans we have identified that the receptor functions in two different modes in different physiological contexts. One mode relays a signal via a classical G protein-mediated cascade (7TM-dependent/cis), the second one is only dependent on the receptor´s N terminus (7TM-independent/trans). The signals behind these modes and their impact are currently one of our main research topics. Similarly, we are elucidating the activation and signal transduction mechanisms of other aGPCRs.

 

Adhesion GPCRs in development and cell polarity

Multicellular organisms are highly dependent on their cells to be spatially organised to form different tissues and organs and to develop/maintain specialised functions. For this organisation cells require a sense of orientation and a form of polarity. Various types of polarity are involved in realising these processes and it is becoming increasingly clear that Adhesion GPCRs (aGPCRs) are vital players with one group of them being Latrophilins. The Latrophilin homologue LAT-1 in C. elegans is a regulator for oriented cell division in the early embryo as well as for correct reproductive system function. We use the nematode C. elegans to delineate and understand the roles of aGPCRs in development and cell polarity. C. elegans is ideal for these studies as it is a transparent self-fertilising organism which is very well characterised and offers a vast spectrum of transgenesis and genetic techniques.

 

Adhesion GPCRs in metabolic processes

Adhesion GPCRs are an intriguing class of receptors. With 33 members in mammals they form the second largest group of GPCRs, but also a poorly understood one. Several aGPCRs have implications in the control of metabolic processes. We aim to uncover the physiological functions several of these receptors play in regulating fat and insulin metabolism as well as kidney function. Thereby, one main focus is on Latrophilins, GPR110, GPR111 and GPR115, which have for instance been shown to regulate insulin release or liver metabolism.

 

Projects

  • Mechanisms of Cis and Trans signaling of Adhesion GPCRs
  • Physiological relevance and signaling mechanisms of the Adhesion GPCR GPR110 (DFG funded)
  • The relevance of Adhesion GPCRs in glucose and energy homeostasis (ESF funded)
  • In vivo analysis of the signal transduction of neuropeptide receptors in Caenorhabditis elegans (SMWK funded)

 

Team

  • Dr. Simone Prömel (Junior Group Leader)
  • Dr. Sandra Huth (Postdoc)
  • Lidia Duplice (PhD student)
  • Victoria Groß (PhD student)
  • Franziska Münzner (nee Fiedler, PhD student)
  • Daniel Matúš (MD student)
  • Johanna Schön (MD student)
  • Claudia Binder (technician)

 

Johanna Weinert/Sandra Huth/Lidia Duplice/Claudia Binder/Victoria Groß/Johanna Schön/Simone Prömel/Daniel Matúš

Publications

 

  1. Gershkovich MM, Groß VE, Kaiser A, Prömel S. Pharmacological and functional similarities of the human neuropeptide Y system in C. elegans challenges phylogenetic views on the FLP/NPR system. Cell Commun Signal. 2019; 17: 123.
  2. Heshof R, Visscher B, Prömel S, Hughes S (2019) Large-scale cultivation of Caenorhabditis elegans in a bioreactor using a labor-friendly fed-batch approach. Biotechniques. doi: 10.2144/btn-2019-0008. [Epub ahead of print].
  3. Morgan RK, Anderson GR, Araç D, Aust G, Balenga N, Boucard A, Bridges JP, Engel FB, Formstone CJ, Glitsch MD, Gray RS, Hall RA, Hsiao CC, Kim HY, Knierim AB, Kusuluri DK, Leon K, Liebscher I, Piao X, Prömel S, Scholz N, Srivastava S,Thor D, Tolias KF, Ushkaryov YA, Vallon M, Van Meir EG, Vanhollebeke B, Wolfrum U, Wright KM, Monk KR, Mogha A. The expanding functional roles and signaling mechanisms of adhesion G protein-coupled receptors. Annals of the New York Academy of Sciences. 2019; doi: 10.1111/nyas.14094. [Epub ahead of print].
  4. Schöneberg T, Prömel S (2019) Latrophilins and Teneurins in invertebrates: no love for each other? Front. Neurosci.13:154.
  5. Röthe J, Thor D, Winkler J, Knierim AB, Binder C, Huth S, Kraft R, Rothemund S, Schöneberg T, Prömel S (2019) Involvement of the Adhesion GPCRs Latrophilins in the Regulation of Insulin Release. Cell Reports 26(6):1573-1584.
  6. Matúš D, Prömel S (2018) G Proteins and GPCRs in C. elegans Development: A Story of Mutual Infidelity. J Dev Biol. 6(4)
  7. Nazarko O, Kibrom A, Winkler J, Stoveken H, Leon K, Salzman G, Merdas K, Lu Y, Narkhede P, Tall G, Prömel S, Araç D (2018) A comprehensive mutagenesis screen of the adhesion GPCR Latrophilin-1/ADGRL1. iScience 3:264-278.
  8. Scholz N, Guan C, Nieberler M, Grotemeyer A, Maiellaro I, Gao S, Beck S, Pawlak M, Sauer M, Asan E, Rothemund S, Winkler J, Prömel S, Nagel G, Langenhan T, Kittel RJ (2017) Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons. Elife 8;6. pii: e28360.
  9. Demberg LM, Winkler J, Wilde C, Simon KU, Schön J, Rothemund S, Schöneberg T, Prömel S#, Liebscher I# (2017) Activation of adhesion GPCRs: agonist specificity of Stachel sequence-derived peptides. J Biol Chem. 17;292(11):4383-4394. # equal contribution and shared correspondence
  10. Merkwitz C, Blaschuk O, Winkler J, Schulz A, Prömel S, Ricken AM (2017) Advantages and limitations of salmon-Gal/tetrazolium salt histochemistry for the detection of LacZ reporter gene activity in murine epithelial tissue. J Histochem Cytochem. 65(4):197-206.
  11. Strutt D, Schnabel R, Fiedler F, Prömel S (2016) Adhesion GPCRs Govern Polarity of Epithelia and Cell Migration. In: Langenhan, Schöneberg (Eds.) Adhesion G Protein-coupled Receptors, Handbook of Experimental Pharmacology Vol. 234, Springer International Publishing Switzerland.
  12. Prömel S#, Fiedler F, Binder C, Schöneberg T, Thor D# (2016) Deciphering and modulating G protein signalling in C. elegans using the DREADD technology. Sci Rep. 27;6:28901 # equal contribution and shared correspondence
  13. Winkler J, Prömel S (2016) The adhesion GPCR latrophilin – a novel signaling cascade in oriented cell division and anterior-posterior polarity. Worm 5(2) e1170274.
  14. Merkwitz C, Blaschuk O, Eplinius F, Winkler J, Prömel S, Schulz A, Ricken A (2015) A simple method for inducing estrous cycle stage-specific morphological changes in the vaginal epithelium of immature female mice. Lab Anim. 0023677215617387.
  15. Müller A, Winkler J, Fiedler F, Sastradihardja T, Binder C, Schnabel R, Kungel J, Rothemund S, Hennig C, Schöneberg T, Prömel S (2015) Oriented cell division in the C. elegans embryo Is coordinated by G-protein signaling dependent on the Adhesion GPCR LAT-1. PLoS Genet. 11(10):e1005624.
  16. Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin HH, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, Schiöth HB (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol Rev. 67(2):338-67.
  17. Liebscher I, Ackley B, Araç D, Ariestanti DM, Aust G, Bae BI, Bista BR, Bridges JP, Duman JG, Engel FB, Giera S, Goffinet AM, Hall RA, Hamann J, Hartmann N, Lin HH, Liu M, Luo R, Mogha A, Monk KR, Peeters MC, Prömel S, Ressl S, Schiöth HB, Sigoillot SM, Song H, Talbot WS, Tall GG, White JP, Wolfrum U, Xu L, Piao X (2014) New functions and signaling mechanisms for the class of adhesion G protein-coupled receptors. Ann N Y Acad Sci.1333:43-64.
  18. Prömel S, Langenhan T, Araç D (2013) Matching structure with function: the GAIN domain of Adhesion-GPCR and PKD1-like proteins. Trends Pharmacol Sci. 34(8):470-8.
  19. Liebscher I, Schöneberg T, Prömel S (2013) Progress in demystification of adhesion GPCR. Biol Chem 394(8): 937-950.
  20. Araç D, Aust G, Calebiro D, Engel FB, Formstone C, Goffinet A, Hamann J, Kittel RJ, Liebscher I, Lin HH, Monk KR, Petrenko A, Piao X, Prömel S, Schiöth HB, Schwartz TW, Stacey M, Ushkaryov YA, Wobus M, Wolfrum U, Xu L, Langenhan T (2012) Dissecting signaling and functions of adhesion G protein-coupled receptors. Ann N Y Acad Sci. 1276:1-25.
  21. Prömel S, Frickenhaus M, Hughes S, Mestek L, Staunton D, Woollard A, Vakonakis I, Schöneberg T, Schnabel R, Russ AP, Langenhan T (2012) The GPS motif is a molecular switch for bimodal activities of Adhesion-class G protein-coupled receptors. Cell Reports 2(2): 321-331.
  22. Prömel S#, Waller-Evans H, Dixon J, Zahn D, Colledge WH, Doran J, Carlton MBL, Grosse J, Schöneberg T, Russ AP, Langenhan T# (2012) Characterization and functional study of a cluster of four highly conserved orphan adhesion-GPCR in mouse. Dev Dyn. 241(10):1591-1602. #shared correspondence
  23. Gregory AP, Dendrou CA, Attfield KE, Haghikia A, Xifara DK, Butter F, Poschmann G, Kaur G, Lambert L, Leach OA, Prömel S, Punwani D, Felce JH, Davis SJ, Gold R, Nielsen FC, Siegel RM, Mann M, Bell JI, McVean G, Fugger L (2012) TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 488(7412):508-11.
  24. Waller-Evans H, Prömel S, Langenhan T, Dixon J, Zahn D, Colledge WH, Doran J, Carlton MB, Davies B, Aparicio SA, Grosse J, Russ AP (2010) The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse. PLoS One 18;5(11):e14047.
  25. Langenhan T, Prömel S, Mestek L, Esmaeili B, Waller-Evans H, Hennig C, Kohara Y, Avery L, Vakonakis I, Schnabel R, Russ AP (2009) Latrophilin signaling links anterior-posterior tissue polarity and oriented cell divisions in the C. elegans embryo. Dev Cell 17(4):494-504.
  26. Vakonakis I, Langenhan T, Prömel S, Russ A, Campbell ID (2008) Solution Structure and Sugar-Binding Mechanism of Mouse Latrophilin-1 RBL: a 7TM Receptor-Attached Lectin-Like Domain. Structure 16(6):944-953.