PXD053405-1

PXD053405 is an original dataset announced via ProteomeXchange.

Title	GUK1 activation is a metabolic liability in oncogene-driven lung cancer
Description	Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we performed a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged (“ALK+”) patient-derived cell lines and identified guanylate kinase 1 (GUK1), a GDP-synthesizing enzyme, as a novel target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatially resolved mass spectrometry imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ. Abrogation of GUK1 phosphorylation reduces intracellular GDP and GTP pools and decreases MAPK signaling through impaired Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo. Beyond ALK, we determined that other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.
HostingRepository	PRIDE
AnnounceDate	2025-01-29
AnnouncementXML	Submission_2025-01-29_07:33:54.280.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joao Paulo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-25 13:59:53	ID requested
⏵ 1	2025-01-29 07:33:54	announced

Dataset with its publication pending

submitter keyword: purine nucleotides, guanylate kinase 1 (GUK1), metabolic dependency, tyrosine kinase inhibitor (TKI),Lung cancer, non-small cell lung cancer (NSCLC), guanosine diphosphate (GDP), tumor metabolism, Ras, signaling, anaplastic lymphoma kinase (ALK)

Jaime Laurel Schneider, M.D. Ph.D.
contact affiliation	Center for Thoracic Cancers, MGH Cancer Center Massachusetts General Hospital Harvard Medical School USA
contact email	JSchneider@mgh.harvard.edu
lab head
Joao Paulo
contact affiliation	Harvard Medical School
contact email	joao_paulo@post.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD053405
     1. Label: PRIDE project
     2. Name: GUK1 activation is a metabolic liability in oncogene-driven lung cancer