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PreprintCited by 5Protein Tyrosine PhosphatasesCancer-related Molecular PathwaysProtein Kinase Regulation and GTPase Signaling

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A PTP1B-Cdk3 signaling axis promotes cell cycle progression of human glioblastoma cells through an Rb-E2F dependent pathway

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Villamar-Cruz, Olga, Loza-Mejía, Marco Antonio, Vivar-Sierra, Alonso, Saldivar-Cerón, Héctor Iván, Patiño-López, Genaro, Efraín Olguín, Jonadab, Terrazas, Luis Ignacio, Armas-López, Leonel, Ávila-Moreno, Federico, Saha, Sayanti, Chernoff, Jonathan, Camacho-Arroyo, Ignacio, Arias-Romero, Luis Enrique·2022·Molecular and Cellular Biology
DOI 10.1101/2022.06.14.496178PMC PMC10761042

Preprint — published as 10.1080/10985549.2023.2273193

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Abstract

Protein tyrosine phosphatase 1B (PTP1B) plays a key role in developing different types of cancer. However, the molecular mechanism underlying this effect is unclear. To identify possible molecular targets of PTP1B that mediate its positive role in tumorigenesis, we undertook a SILAC-based phosphoproteomic approach, which allowed us to identify the Cyclin-dependent kinase 3 (Cdk3) as a novel PTP1B substrate. Molecular docking studies revealed stable interactions between the PTP1B catalytic domain and Cdk3. In addition, we observed that PTP1B dephosphorylates a Cdk3 derived peptide at Tyrosine residue 15 in vitro and interacts with endogenous Cdk3 in the nucleus and cytoplasm of human glioblastoma (GB) cells. Finally, we found that the pharmacological inhibition of PTP1B or its depletion with siRNA leads to cell cycle arrest with the diminished activity of Cdk3, the consequent hypophosphorylation of Rb, and the down-regulation of E2F and its target genes Cdk1, Cyclin A, and Cyclin E1. These data delineate a novel signaling pathway from PTP1B to Cdk3 required for efficient cell cycle progression in an Rb-E2F dependent manner in human GB cells and suggest new therapeutic strategies for treating these tumors.

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Metadata

Authors
Villamar-Cruz, O., Loza-Mejía, M. A., Vivar-Sierra, A., Saldivar-Cerón, H. I., Patiño-López, G., Efraín Olguín, J., Terrazas, L. I., Armas-López, L., Ávila-Moreno, F., Saha, S., Chernoff, J., Camacho-Arroyo, I., & Arias-Romero, L. E.
Affiliations
  • Universidad La Salle (MX)
  • Universidad Nacional Autónoma de México, Facultad de Estudios Superiores Iztacala (MX)
  • Fox Chase Cancer Center (US)
Corresponding author
Chernoff, Jonathan
ORCID
Venue
Molecular and Cellular Biology
Publisher
openRxiv
Published
2022-06-16
Volume
43
Issue
12
Pages
631-649
ISSN
0270-7306 (ISSN-L)
DOI
10.1101/2022.06.14.496178
PMC
PMC10761042
OpenAlex
W4389084948
Cited by
5
References
1
Citations by year
2026: 3 · 2025: 2
FWCI
0.45
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Molecular and Cellular Biology (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Hawaii Invasive Species Council
  • National Institutes of Health
  • Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México (IN217120)
  • National Cancer Institute (R01CA117884)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
PTP1B, CDK3, glioblastoma, cell cycle progression, Rb/E2F pathway, tyrosine dephosphorylation, protein phosphatase, E2F target genes, cyclin A, cyclin E1, CDK1, protein-protein interaction, phosphoproteomics
MeSH terms
Cell Cycle, Cell Division, Glioblastoma, Humans, Signal Transduction, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Cell Cycle Checkpoints

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