TY - JOUR
T1 - Unbiased identification of substrates of protein tyrosine phosphatase ptp-3 in C. elegans
AU - Mitchell, Christopher J.
AU - Kim, Min Sik
AU - Zhong, Jun
AU - Nirujogi, Raja Sekhar
AU - Bose, Anjun K.
AU - Pandey, Akhilesh
N1 - Funding Information:
This study was supported by NCI's Clinical Proteomic Tumor Analysis Consortium initiative ( U24CA160036 ).
Publisher Copyright:
© 2016 Federation of European Biochemical Societies.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - Phosphoproteomics
KW - Protein tyrosine phosphatases
KW - Tyrosine phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=84962136658&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84962136658&partnerID=8YFLogxK
U2 - 10.1016/j.molonc.2016.03.003
DO - 10.1016/j.molonc.2016.03.003
M3 - Article
C2 - 27067626
AN - SCOPUS:84962136658
SN - 1574-7891
VL - 10
SP - 910
EP - 920
JO - Molecular Oncology
JF - Molecular Oncology
IS - 6
ER -