VLK drives extracellular phosphorylation of EphB2 to govern the EphB2-NMDAR interaction and injury-induced pain

Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families, yet the significance of these kinases is underexplored. Here, we find that the presynaptic release of the tyrosine directed-ectokinase, Vertebrate Lonesome Kinase (VLK/Pkdcc), is necessary and sufficient...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Srikanth, Kolluru D, Elahi, Hajira, Chander, Praveen, Washburn, Halley R, Hassler, Shayne, Mwirigi, Juliet M, Kume, Moeno, Loucks, Jessica, Arjarapu, Rohita, Hodge, Rachel, Shiers, Stephanie I, Sankaranarayanan, Ishwarya, Erdjument-Bromage, Hediye, Neubert, Thomas A, Campbell, Zachary T, Paik, Raehum, Price, Theodore J, Dalva, Matthew B
Format Journal Article
LanguageEnglish
Published United States 18.03.2024
Online AccessGet full text

Cover

Loading…
Abstract Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families, yet the significance of these kinases is underexplored. Here, we find that the presynaptic release of the tyrosine directed-ectokinase, Vertebrate Lonesome Kinase (VLK/Pkdcc), is necessary and sufficient for the direct extracellular interaction between EphB2 and GluN1 at synapses, for phosphorylation of the ectodomain of EphB2, and for injury-induced pain. is an essential gene in the nervous system, and VLK is found in synaptic vesicles, and is released from neurons in a SNARE-dependent fashion. VLK is expressed by nociceptive sensory neurons where presynaptic sensory neuron-specific knockout renders mice impervious to post-surgical pain, without changing proprioception. VLK defines an extracellular mechanism that regulates protein-protein interaction and non-opioid-dependent pain in response to injury.
AbstractList Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families, yet the significance of these kinases is underexplored. Here, we find that the presynaptic release of the tyrosine directed-ectokinase, Vertebrate Lonesome Kinase (VLK/Pkdcc), is necessary and sufficient for the direct extracellular interaction between EphB2 and GluN1 at synapses, for phosphorylation of the ectodomain of EphB2, and for injury-induced pain. Pkdcc is an essential gene in the nervous system, and VLK is found in synaptic vesicles, and is released from neurons in a SNARE-dependent fashion. VLK is expressed by nociceptive sensory neurons where presynaptic sensory neuron-specific knockout renders mice impervious to post-surgical pain, without changing proprioception. VLK defines an extracellular mechanism that regulates protein-protein interaction and non-opioid-dependent pain in response to injury.Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families, yet the significance of these kinases is underexplored. Here, we find that the presynaptic release of the tyrosine directed-ectokinase, Vertebrate Lonesome Kinase (VLK/Pkdcc), is necessary and sufficient for the direct extracellular interaction between EphB2 and GluN1 at synapses, for phosphorylation of the ectodomain of EphB2, and for injury-induced pain. Pkdcc is an essential gene in the nervous system, and VLK is found in synaptic vesicles, and is released from neurons in a SNARE-dependent fashion. VLK is expressed by nociceptive sensory neurons where presynaptic sensory neuron-specific knockout renders mice impervious to post-surgical pain, without changing proprioception. VLK defines an extracellular mechanism that regulates protein-protein interaction and non-opioid-dependent pain in response to injury.
Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families, yet the significance of these kinases is underexplored. Here, we find that the presynaptic release of the tyrosine directed-ectokinase, Vertebrate Lonesome Kinase (VLK/Pkdcc), is necessary and sufficient for the direct extracellular interaction between EphB2 and GluN1 at synapses, for phosphorylation of the ectodomain of EphB2, and for injury-induced pain. is an essential gene in the nervous system, and VLK is found in synaptic vesicles, and is released from neurons in a SNARE-dependent fashion. VLK is expressed by nociceptive sensory neurons where presynaptic sensory neuron-specific knockout renders mice impervious to post-surgical pain, without changing proprioception. VLK defines an extracellular mechanism that regulates protein-protein interaction and non-opioid-dependent pain in response to injury.
Author Shiers, Stephanie I
Dalva, Matthew B
Arjarapu, Rohita
Hassler, Shayne
Elahi, Hajira
Paik, Raehum
Neubert, Thomas A
Kume, Moeno
Price, Theodore J
Washburn, Halley R
Loucks, Jessica
Chander, Praveen
Srikanth, Kolluru D
Hodge, Rachel
Erdjument-Bromage, Hediye
Mwirigi, Juliet M
Campbell, Zachary T
Sankaranarayanan, Ishwarya
Author_xml – sequence: 1
  givenname: Kolluru D
  surname: Srikanth
  fullname: Srikanth, Kolluru D
  organization: Jefferson Synaptic Biology Center, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107
– sequence: 2
  givenname: Hajira
  surname: Elahi
  fullname: Elahi, Hajira
  organization: Center for Advanced Pain Studies, University of Texas at Dallas; Richardson, TX 75080, USA
– sequence: 3
  givenname: Praveen
  surname: Chander
  fullname: Chander, Praveen
  organization: Jefferson Synaptic Biology Center, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107
– sequence: 4
  givenname: Halley R
  surname: Washburn
  fullname: Washburn, Halley R
  organization: Department of Molecular Biology, Princeton University; Princeton, NJ 08544, USA
– sequence: 5
  givenname: Shayne
  surname: Hassler
  fullname: Hassler, Shayne
  organization: College of Medicine, University of Houston; Houston, TX 77004, USA
– sequence: 6
  givenname: Juliet M
  surname: Mwirigi
  fullname: Mwirigi, Juliet M
  organization: Center for Advanced Pain Studies, University of Texas at Dallas; Richardson, TX 75080, USA
– sequence: 7
  givenname: Moeno
  surname: Kume
  fullname: Kume, Moeno
  organization: Center for Advanced Pain Studies, University of Texas at Dallas; Richardson, TX 75080, USA
– sequence: 8
  givenname: Jessica
  surname: Loucks
  fullname: Loucks, Jessica
  organization: Department of Neuroscience, The University of Texas at Dallas; Richardson, TX 75080, USA
– sequence: 9
  givenname: Rohita
  surname: Arjarapu
  fullname: Arjarapu, Rohita
  organization: Department of Neuroscience, The University of Texas at Dallas; Richardson, TX 75080, USA
– sequence: 10
  givenname: Rachel
  surname: Hodge
  fullname: Hodge, Rachel
  organization: Jefferson Synaptic Biology Center, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107
– sequence: 11
  givenname: Stephanie I
  surname: Shiers
  fullname: Shiers, Stephanie I
  organization: Center for Advanced Pain Studies, University of Texas at Dallas; Richardson, TX 75080, USA
– sequence: 12
  givenname: Ishwarya
  surname: Sankaranarayanan
  fullname: Sankaranarayanan, Ishwarya
  organization: Center for Advanced Pain Studies, University of Texas at Dallas; Richardson, TX 75080, USA
– sequence: 13
  givenname: Hediye
  surname: Erdjument-Bromage
  fullname: Erdjument-Bromage, Hediye
  organization: Department of Neuroscience and Physiology and Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, 10016, USA
– sequence: 14
  givenname: Thomas A
  surname: Neubert
  fullname: Neubert, Thomas A
  organization: Department of Neuroscience and Physiology and Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, 10016, USA
– sequence: 15
  givenname: Zachary T
  surname: Campbell
  fullname: Campbell, Zachary T
  organization: Department of Anesthesiology, University of Wisconsin-Madison; Madison, WI 53792, USA
– sequence: 16
  givenname: Raehum
  surname: Paik
  fullname: Paik, Raehum
  organization: Department of Genetics, University of Texas Health Science Center at San Antonio; San Antonio, TX 78229, USA
– sequence: 17
  givenname: Theodore J
  orcidid: 0000-0002-6971-6221
  surname: Price
  fullname: Price, Theodore J
  organization: Center for Advanced Pain Studies, University of Texas at Dallas; Richardson, TX 75080, USA
– sequence: 18
  givenname: Matthew B
  surname: Dalva
  fullname: Dalva, Matthew B
  organization: Jefferson Synaptic Biology Center, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107
BackLink https://www.ncbi.nlm.nih.gov/pubmed/38562765$$D View this record in MEDLINE/PubMed
BookMark eNpNkEtPwzAQhC1UREvpD-CCfOSS4EfsxMdSykMUkBBwrZx4Q1OldrCTiv57AgWJw2h3Vp9G2jlGA-ssIHRKSUwpoReMsCQmPKZZLDLBaXKARkwqFmWMiMG_fYgmIawJIUxJytPkCA15JiRLpRgh97a4x8ZXWwgYPluvC6jrrtYeNysXevldrdvKWexKPG9Wlwy3Dr-7LXiL2xXsb9Hjw9X0GVe2hT7hB9fW9H7d-V1UWdMVYHCjK3uCDktdB5j8zjF6vZ6_zG6jxdPN3Wy6iBoqRBLlUhiTKJmCpqRIeVlIWQqTFkLntFQkJ6IQTBUATKQZJ4YkJQAQmidSJYrzMTrf5zbefXQQ2uWmCt-_aQuuC0tOOKWcKJr26Nkv2uUbMMvGVxvtd8u_kvgXx19rrw
ContentType Journal Article
DBID NPM
7X8
DOI 10.1101/2024.03.18.585314
DatabaseName PubMed
MEDLINE - Academic
DatabaseTitle PubMed
MEDLINE - Academic
DatabaseTitleList MEDLINE - Academic
PubMed
Database_xml – sequence: 1
  dbid: NPM
  name: PubMed
  url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
  sourceTypes: Index Database
DeliveryMethod fulltext_linktorsrc
Discipline Biology
EISSN 2692-8205
ExternalDocumentID 38562765
Genre Preprint
GrantInformation_xml – fundername: NINDS NIH HHS
  grantid: R01 NS111976
– fundername: NINDS NIH HHS
  grantid: R01 NS114018
– fundername: NINDS NIH HHS
  grantid: R01 NS115441
– fundername: NCRR NIH HHS
  grantid: S10 RR027990
GroupedDBID 8FE
8FH
AFKRA
ALMA_UNASSIGNED_HOLDINGS
BBNVY
BENPR
BHPHI
HCIFZ
LK8
M7P
NPM
NQS
PIMPY
PROAC
RHI
7X8
ID FETCH-LOGICAL-p1554-b65dd4967ea10c73fc66f5d7c5ab1f90b05c529cee257830d04feee01b4694933
ISSN 2692-8205
IngestDate Sat Nov 23 00:00:27 EST 2024
Thu Nov 28 21:26:38 EST 2024
IsDoiOpenAccess false
IsOpenAccess true
IsPeerReviewed false
IsScholarly false
Language English
LinkModel OpenURL
MergedId FETCHMERGED-LOGICAL-p1554-b65dd4967ea10c73fc66f5d7c5ab1f90b05c529cee257830d04feee01b4694933
Notes ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Working Paper/Pre-Print-1
content type line 23
ORCID 0000-0002-6971-6221
OpenAccessLink https://www.biorxiv.org/content/biorxiv/early/2024/03/18/2024.03.18.585314.full.pdf
PMID 38562765
PQID 3031130917
PQPubID 23479
ParticipantIDs proquest_miscellaneous_3031130917
pubmed_primary_38562765
PublicationCentury 2000
PublicationDate 2024-Mar-18
20240318
PublicationDateYYYYMMDD 2024-03-18
PublicationDate_xml – month: 03
  year: 2024
  text: 2024-Mar-18
  day: 18
PublicationDecade 2020
PublicationPlace United States
PublicationPlace_xml – name: United States
PublicationTitle bioRxiv
PublicationTitleAlternate bioRxiv
PublicationYear 2024
SSID ssj0002961374
Score 1.9158309
Snippet Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families, yet the significance of these kinases is underexplored. Here,...
SourceID proquest
pubmed
SourceType Aggregation Database
Index Database
Title VLK drives extracellular phosphorylation of EphB2 to govern the EphB2-NMDAR interaction and injury-induced pain
URI https://www.ncbi.nlm.nih.gov/pubmed/38562765
https://www.proquest.com/docview/3031130917
hasFullText 1
inHoldings 1
isFullTextHit
isPrint
link http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnZ1db9MwFIat0gmJG8Q32wAZiTuU4SSOE9-xQaaJlYKqFvUushObdlRJlLWI8es5trO0pSANLhpVlhIrfqKT9zjnA6FXINiUFgnzijyWHpVF4HEVRF6ehIJRTYkqbJTvkJ1N6IdpNO313m5mlyzlUf7zj3kl_0MVxoCryZL9B7LdRWEA_gNfOAJhON6I8ZfB-euisYVjwcY2wuzC27DSelZdwq-5WnSKMK1nJ4FRml9td10rOO2YN_z4_nhk60Y0143DbUWmC1huD1z2lQkRqEVborsVsnJejX7Mv3cbNM38GzCyezTnpntys1rHEqcLMXPNscXFvFmHBs1sZo3VsaYJ0jopzXR4AtilO2dh7NZoc3sioCY-a9OiBoyDyQ2I-3Stdsd2bbjtHWCuZcrP-skReDShyzTdrpc9_JSdTgaDbJxOx7fQnimFSPto7yQdfh51-2wBB8Fii3F3s7Yft2GeNzuz_N3RsIJjfA_dbT0FfOyw30c9VT5At13v0KuHqAL42MHHW_Dxb_BxpbEFjZcVdvAxwMcb8PEGfAxQ8DZ8bOA_QpPTdPzuzGu7Z3i10YieZFFRUM5iJXySx6HOGdNREeeRkL7mRJIojwIOIslY7ZAUhGqlFPElZZzyMHyM-mVVqqcIKwKyWGjBY_A-Iz-WNGQ6L7SfCHiXEn8fvbxetAysk7lfUapqdZmBQPJBJXE_3kdP3GpmtSujkoUJaO-YRQc3OPsQ3Vk_XM9Qf9ms1HNQg0v5ogX-CxBzX-Y
link.rule.ids 314,780,784,27924,27925,33745
linkProvider ProQuest
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=VLK+drives+extracellular+phosphorylation+of+EphB2+to+govern+the+EphB2-NMDAR+interaction+and+injury-induced+pain&rft.jtitle=bioRxiv&rft.au=Srikanth%2C+Kolluru+D&rft.au=Elahi%2C+Hajira&rft.au=Chander%2C+Praveen&rft.au=Washburn%2C+Halley+R&rft.date=2024-03-18&rft.issn=2692-8205&rft.eissn=2692-8205&rft_id=info:doi/10.1101%2F2024.03.18.585314&rft.externalDBID=NO_FULL_TEXT
thumbnail_l http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=2692-8205&client=summon
thumbnail_m http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=2692-8205&client=summon
thumbnail_s http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=2692-8205&client=summon