The Parkinson's-disease-associated receptor GPR37 undergoes metalloproteinase-mediated N-terminal cleavage and ectodomain shedding

Mattila, Sampo; Tuusa, Jussi; Petäjä-Repo, Ulla E.

doi:10.1242/jcs.176115

Cited by 29 publications

(57 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is not unexpected; there is no clear consensus sequence for ADAM or MMP cleavage (36) and amino acid substitutions both within and at variable proximity to the cleaved residues are well tolerated (41). Furthermore, a similar study of N-terminal proteolysis was also unable to prevent receptor cleavage by mutagenesis for the closely related GPR37 (40). Thus, the precise site of GPR37L1 N-terminal cleavage and the identity of the specific protease(s) responsible remain undefined.…”

Section: Discussionmentioning

confidence: 99%

The N-terminus of GPR37L1 is proteolytically processed by matrix metalloproteases

Coleman

Ngo

Smythe

et al. 2020

Preprint

View full text Add to dashboard Cite

GPR37L1 is an orphan G protein-coupled receptor expressed exclusively in the brain and linked to seizures, neuroprotection and cardiovascular disease. Based upon the observation that fragments of the GPR37L1 N-terminus are found in human cerebrospinal fluid, we hypothesized that GPR37L1 was subject to post-translational modification. Heterologous expression of GPR37L1-eYFP in either HEK293 or U87 glioblastoma cells yielded two cell surface species of approximately equivalent abundance, the larger of which is N-glycosylated at Asn 105 . The smaller species is produced by matrix metalloprotease/ADAMmediated proteolysis (shown by the use of pharmacological inhibitors) and has a molecular weight identical to that of a mutant lacking the entire N-terminus, Δ122 GPR37L1. Serial truncation of the Nterminus prevented GPR37L1 expression except when the entire N-terminus was removed, narrowing the predicted site of N-terminal proteolysis to residues 105-122. Using yeast expressing different G protein chimeras, we found that wild type GPR37L1, but not Δ122 GPR37L1, coupled constitutively to Gpa1/Gαs and Gpa1/Gα16 chimeras, in contrast to previous studies. We tested the peptides identified in cerebrospinal fluid as well as their putative newly-generated N-terminal 'tethered' counterparts in both wild type and Δ122 GPR37L1 Gpa1/Gαs strains but saw no effect, suggesting that GPR37L1 does not signal in a manner akin to the protease-activated receptor family. We also saw no evidence of receptor activation or regulation by the reported GPR37L1 ligand, prosaptide/TX14A. Finally, the proteolytically processed species predominated both in vivo and ex vivo in organotypic cerebellar slice preparations, suggesting that GPR37L1 is rapidly processed to a signaling-inactive form. Our data indicate that the function of GPR37L1 in vivo is tightly regulated by metalloprotease-dependent N-terminal cleavage.

show abstract

Section: Discussionmentioning

confidence: 99%

The N-terminus of GPR37L1 is proteolytically processed by matrix metalloproteases

Coleman

Ngo

Smythe

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Moreover, on the background of their high constitutive activity, TX14(A) was ineffective (Coleman et al, 2016;Giddens et al, 2017;Ngo et al, 2017). Regulation of this constitutive activity was suggested to occur via cleavage of the extracellular part of GPR37L1 (Coleman et al, 2016;Mattila, Tuusa, & Petaja-Repo, 2016). These reports reinforced the skepticism based on the failure of TX14(A) to activate GPR37L1/GPR37 using the DiscoverX orphan receptorscreening panel (Smith, 2015;Southern et al, 2013).…”

mentioning

confidence: 96%

Glio‐ and neuro‐protection by prosaposin is mediated by orphan G‐protein coupled receptors GPR37L1 and GPR37

Liu

Mosienko

Cardoso

et al. 2018

Glia

View full text Add to dashboard Cite

Discovery of neuroprotective pathways is one of the major priorities for neuroscience. Astrocytes are natural neuroprotectors and it is likely that brain resilience can be enhanced by mobilizing their protective potential. Among G‐protein coupled receptors expressed by astrocytes, two highly related receptors, GPR37L1 and GPR37, are of particular interest. Previous studies suggested that these receptors are activated by a peptide Saposin C and its neuroactive fragments (prosaptide TX14(A)), which were demonstrated to be neuroprotective in various animal models by several groups. However, pairing of Saposin C or prosaptides with GPR37L1/GPR37 has been challenged and presently GPR37L1/GPR37 have regained their orphan status. Here, we demonstrate that in their natural habitat, astrocytes, these receptors mediate a range of effects of TX14(A), including protection from oxidative stress. The Saposin C/GPR37L1/GPR37 pathway is also involved in the neuroprotective effect of astrocytes on neurons subjected to oxidative stress. The action of TX14(A) is at least partially mediated by Gi‐proteins and the cAMP‐PKA axis. On the other hand, when recombinant GPR37L1 or GPR37 are expressed in HEK293 cells, they are not functional and do not respond to TX14(A), which explains unsuccessful attempts to confirm the ligand‐receptor pairing. Therefore, this study identifies GPR37L1/GPR37 as the receptors for TX14(A), and, by extension of Saposin C, and paves the way for the development of neuroprotective therapeutics acting via these receptors. A video abstract of this article can be found at: https://www.youtube.com/watch?v=qTn13My9Sz8

show abstract

“…Consequently, levels of mature LRP6 are reduced and Wnt/β‐catenin signaling is inhibited (see model in Synopsis). Interestingly, the N‐terminal domain of GPR37 undergoes metalloprotease‐dependent cleavage , which mediates its localization . However, this occurs during GPR37 transit through the Golgi, after it functions in the ER to promote LRP6 maturation.…”

Section: Resultsmentioning

confidence: 99%

Parkinson's disease‐associated receptor GPR 37 is an ER chaperone for LRP 6

et al. 2017

View full text Add to dashboard Cite

Wnt/b-catenin signaling plays a key role in embryonic development, stem cell biology, and neurogenesis. However, the mechanisms of Wnt signal transmission, notably how the receptors are regulated, remain incompletely understood. Here we describe that the Parkinson's disease-associated receptor GPR37 functions in the maturation of the N-terminal bulky b-propellers of the Wnt coreceptor LRP6. GPR37 is required for Wnt/b-catenin signaling and protects LRP6 from ER-associated degradation via CHIP (carboxyl terminus of Hsc70-interacting protein) and the ATPase VCP. GPR37 is highly expressed in neural progenitor cells (NPCs) where it is required for Wnt-dependent neurogenesis. We conclude that GPR37 is crucial for cellular protein quality control during Wnt signaling.

show abstract

The Parkinson's-disease-associated receptor GPR37 undergoes metalloproteinase-mediated N-terminal cleavage and ectodomain shedding

Cited by 29 publications

References 57 publications

The N-terminus of GPR37L1 is proteolytically processed by matrix metalloproteases

The N-terminus of GPR37L1 is proteolytically processed by matrix metalloproteases

Glio‐ and neuro‐protection by prosaposin is mediated by orphan G‐protein coupled receptors GPR37L1 and GPR37

Parkinson's disease‐associated receptor GPR 37 is an ER chaperone for LRP 6

Contact Info

Product

Resources

About