Unbiased identification of substrates of protein tyrosine phosphatase ptp-3 in C. elegans

Christopher J. Mitchell, Min Sik Kim, Jun Zhong, Raja Sekhar Nirujogi, Anjun K. Bose, Akhilesh Pandey

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The leukocyte antigen related (LAR) family of receptor-like protein tyrosine phosphatases has three members in humans - PTPRF, PTPRD and PTPRS - that have been implicated in diverse processes including embryonic development, inhibition of cell growth and axonal guidance. Mutations in the LAR family are associated with developmental defects such as cleft palate as well as various cancers including breast, neck, lung, colon and brain. Although this family of tyrosine phosphatases is important for many developmental processes, little is known of their substrates. This is partially due to functional redundancy within the LAR family, as deletion of a single gene in the LAR family does not have an appreciable phenotype, but a dual knockout is embryonically lethal in mouse models. To circumvent the inability to knockout multiple members of the LAR family in mouse models, we used a knockout of ptp-3, which is the only known ortholog of the LAR family in Caenorhabditis elegans and allows for the study of the LAR family at the organismal level. Using SILAC-based quantitative phosphoproteomics, we identified 255 putative substrates of ptp-3, which included four of the nine known annotated substrates of the LAR family. A motif analysis of the identified phosphopeptides allowed for the determination of sequences that appear to be preferentially dephosphorylated. Finally, we discovered that kinases were overrepresented in the list of identified putative substrates and tyrosine residues whose phosphorylation is known to increase kinase activity were dephosphorylated by ptp-3. These data are suggestive of ptp-3 as a potential negative regulator of several kinase families, such as the mitogen activated kinases (MAPKs), and multiple tyrosine kinases including FER, MET, and NTRK2.

Original languageEnglish (US)
Pages (from-to)910-920
Number of pages11
JournalMolecular Oncology
Volume10
Issue number6
DOIs
StatePublished - Jun 1 2016
Externally publishedYes

Fingerprint

Protein Tyrosine Phosphatases
HLA Antigens
Phosphotransferases
Tyrosine
Receptor-Like Protein Tyrosine Phosphatases
Phosphopeptides
Mitogen-Activated Protein Kinase Kinases
Caenorhabditis elegans
Cleft Palate
Mitogens
Phosphoric Monoester Hydrolases
Embryonic Development
Sequence Analysis
Colon
Neck
Phosphorylation
Breast Neoplasms
Phenotype
Lung
Mutation

Keywords

  • Phosphoproteomics
  • Protein tyrosine phosphatases
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

Cite this

Unbiased identification of substrates of protein tyrosine phosphatase ptp-3 in C. elegans. / Mitchell, Christopher J.; Kim, Min Sik; Zhong, Jun; Nirujogi, Raja Sekhar; Bose, Anjun K.; Pandey, Akhilesh.

In: Molecular Oncology, Vol. 10, No. 6, 01.06.2016, p. 910-920.

Research output: Contribution to journalArticle

Mitchell, Christopher J. ; Kim, Min Sik ; Zhong, Jun ; Nirujogi, Raja Sekhar ; Bose, Anjun K. ; Pandey, Akhilesh. / Unbiased identification of substrates of protein tyrosine phosphatase ptp-3 in C. elegans. In: Molecular Oncology. 2016 ; Vol. 10, No. 6. pp. 910-920.
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