PXD032138

PXD032138 is an original dataset announced via ProteomeXchange.

Title	Protein proximity networks and functional evaluation of the Casein Kinase 1 γ family reveals unique roles for CK1γ3 in WNT signaling
Description	The WNT/β-catenin signaling pathway is evolutionarily conserved and controls normal embryonic development, adult tissue homeostasis, and regeneration. Aberrant activation or suppression of WNT signaling contributes to cancer initiation and progression, developmental disorders, neurodegeneration, and bone disease. Despite great need and more than 40 years of research, targeted therapies for the WNT pathway have yet to be fully realized. Kinases are exceptionally druggable and occupy key nodes within the WNT signaling network, but several pathway-relevant kinases remain understudied and ‘dark’. Here we studied the function of the CSNK1g subfamily of human kinases. miniTurbo-based proximity biotinylation and mass spectrometry analysis of CSNK1γ1, CSNK1γ2, and CSNK1γ3 revealed numerous established components of the β-catenin-dependent and independent WNT signaling pathways, as well as novel interactors. In gain-of-function experiments using a panel of transcriptional reporters, CSNK1γ3 but not CSNK1γ1 or CSNK1γ2 activated β-catenin-dependent WNT signaling, with minimal effect on other signaling pathways. Within the family, CSNK1γ3 expression uniquely induced LRP6 phosphorylation. Conversely, siRNA-mediated silencing of CSNK1γ3 alone had no impact on WNT signaling, though co-silencing of all three family members decreased WNT pathway activity. We characterized two moderately selective and potent small molecule inhibitors of the CSNK1γ family. These inhibitors and a CSNK1γ3 kinase dead mutant suppressed but did not eliminate WNT-driven LRP6 phosphorylation and β-catenin stabilization. Our data suggest that while CSNK1γ3 expression uniquely drives pathway activity, potential functional redundancy within the family necessitates loss of all three family members to suppress the WNT signaling pathway.
HostingRepository	PRIDE
AnnounceDate	2022-06-09
AnnouncementXML	Submission_2022-06-09_09:50:55.443.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dennis Goldfarb
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-09 00:39:41	ID requested
⏵ 1	2022-06-09 09:50:56	announced

Agajanian MJ, Potjewyd FM, Bowman BM, Solomon S, LaPak KM, Bhatt DP, Smith JL, Goldfarb D, Axtman AD, Major MB, 3 in WNT signaling. J Biol Chem, 298(6):101986(2022) [pubmed]

submitter keyword: WNT signaling, casein kinase 1 gamma

Ben Major
contact affiliation	Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, Missouri, USA
contact email	bmajor@wustl.edu
lab head
Dennis Goldfarb
contact affiliation	Cell Biology and Physiology Institute for Informatics
contact email	d.goldfarb@wustl.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD032138
     1. Label: PRIDE project
     2. Name: Protein proximity networks and functional evaluation of the Casein Kinase 1 γ family reveals unique roles for CK1γ3 in WNT signaling