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Control of Adhesion GPCR Function Through Proteolytic Processing

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Adhesion G Protein-coupled Receptors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 234))

Graphical Abstract

Proteolytic processing events in adhesion GPCRs. aGPCRs can undergo multiple autoproteolytic (red asterisks) and proteolytic processing events by exogenous proteases (yellow asterisks) that may be involved in signaling events of the receptors.

Abstract

Proteolytic processing is an unusual property of adhesion family G protein-coupled receptors (aGPCRs) that was observed upon their cloning and biochemical characterization.Ever since, much effort has been dedicated to delineate the mechanisms and requirements for cleavage events in the control of aGPCR function. Most notably, all aGPCRs possess a juxtamembrane protein fold, the GPCR autoproteolysis-inducing (GAIN) domain, which operates as an autoprotease for many aGPCR homologs investigated thus far. Analysis of its autoproteolytic reaction, the consequences for receptor fate and function, and the allocation of physiological effects to this peculiar feature of aGPCRs has occupied the experimental agenda of the aGPCR field and shaped our current understanding of the signaling properties and cell biological effects of aGPCRs. Interestingly, individual aGPCRs may undergo additional proteolytic steps, one of them resulting in shedding of the entire ectodomain that is secreted and can function independently. Here, we summarize the current state of knowledge on GAIN domain-mediated and GAIN domain-independent aGPCR cleavage events and their significance for the pharmacological and cellular actions of aGPCRs. Further, we compare and contrast the proteolytic profile of aGPCRs with known signaling routes that are governed through proteolysis of surface molecules such as the Notch and ephrin pathways.

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Acknowledgments

The writing of this manuscript was supported by grants from the Deutsche Forschungsgemeinschaft to R.J.K. and T.L. (Research Unit FOR 2149, Projects P1 [LA 2861/4-1] and P3 [LA 2861/5-1, KI 1460/2-1]; SFB 1047, Project A5; SFB-TR 166 Projects B4 and C3; LA 2861/7-1. A.G.P. acknowledges support from the Russian Science Foundation (14-14-01195), H.-H.L. acknowledges support from the Ministry of Science and Technology, Taiwan (MOST-104-2320-B-182-035-MY3), and the Chang Gung Memorial Hospital (CMRPD1C0633, CMRPD1D0072-3, CMRPD1D0392).

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Authors and Affiliations

  1. Department of Neurophysiology, Institute of Physiology, University of Würzburg, Röntgenring 9, Würzburg, 97070, Germany

    Matthias Nieberler, Robert J. Kittel & Tobias Langenhan

  2. Laboratory of Receptor Cell Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia

    Alexander G. Petrenko

  3. Department of Microbiology and Immunology, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan

    Hsi-Hsien Lin

  4. Chang Gung Immunology Consortium and Department of Anatomic Pathology, Chang Gung Memorial Hospital-Linkou, Tao-Yuan, 333, Taiwan

    Hsi-Hsien Lin

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  1. Matthias Nieberler
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  2. Robert J. Kittel
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  3. Alexander G. Petrenko
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  4. Hsi-Hsien Lin
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  5. Tobias Langenhan
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Correspondence to Hsi-Hsien Lin or Tobias Langenhan .

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  1. Institute of Physiology Department of Neurophysiology, University of Würzburg, Würzburg, Germany

    Tobias Langenhan

  2. Institute of Biochemistry Medical Faculty, University of Leipzig, Leipzig, Germany

    Torsten Schöneberg

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Nieberler, M., Kittel, R.J., Petrenko, A.G., Lin, HH., Langenhan, T. (2016). Control of Adhesion GPCR Function Through Proteolytic Processing. In: Langenhan, T., Schöneberg, T. (eds) Adhesion G Protein-coupled Receptors. Handbook of Experimental Pharmacology, vol 234. Springer, Cham. https://doi.org/10.1007/978-3-319-41523-9_5

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