Reevaluation of the role of LIP-1 as an ERK/MPK-1 dual specificity phosphatase in the C. elegans germline

Debabrata Das, Jacob Seemann, David Greenstein, Tim Schedl, Swathi Arur

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2 Scopus citations


The fidelity of a signaling pathway depends on its tight regulation in space and time. Extracellular signal-regulated kinase (ERK) controls wide-ranging cellular processes to promote organismal development and tissue homeostasis. ERK activation depends on a reversible dual phosphorylation on the TEY motif in its active site by ERK kinase (MEK) and dephosphorylation by DUSPs (dual specificity phosphatases). LIP-1, a DUSP6/7 homolog, was proposed to function as an ERK (MPK-1) DUSP in the Caenorhabditis elegans germline primarily because of its phenotype, which morphologically mimics that of a RAS/let-60 gain-of-function mutant (i.e., small oocyte phenotype). Our investigations, however, reveal that loss of lip-1 does not lead to an increase in MPK-1 activity in vivo. Instead, we show that loss of lip-1 leads to 1) a decrease in MPK-1 phosphorylation, 2) lower MPK-1 substrate phosphorylation, 3) phenocopy of mpk-1 reduction-of-function (rather than gain-of-function) allele, and 4) a failure to rescue mpk-1-dependent germline or fertility defects. Moreover, using diverse genetic mutants, we show that the small oocyte phenotype does not correlate with increased ectopic MPK-1 activity and that ectopic increase in MPK-1 phosphorylation does not necessarily result in a small oocyte phenotype. Together, these data demonstrate that LIP-1 does not function as an MPK-1 DUSP in the C. elegans germline. Our results caution against overinterpretation of the mechanistic underpinnings of orthologous phenotypes, since they may be a result of independent mechanisms, and provide a framework for characterizing the distinct molecular targets through which LIP-1 may mediate its several germline functions.

Original languageEnglish (US)
Article numbere2113649119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - Jan 18 2022

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank N. Silva, Y. Kim, and V. Jantsch for providing the SYP-1, HTP-3, and p-SUN-1(S8) antibodies, respectively. We thank members of the S.A. laboratory for critical discussions during the study. Research reported in this publication was supported by the National Institute of General Medical Sciences of the NIH under Award R01 GM98200 and National Institute of Child Health and Development of the NIH under Award R01 HD101269 from the S.A. laboratory. D.D. is funded through the Odyssey Postdoctoral Fellowship (supported by the Kimberly-Clark Foundation) and MD Anderson Cancer Center. S.A. is an Andrew Sabin Family Foundation Fellow. D.G. is funded by GM57173 from the NIH. T.S. is funded by R01 GM100756. Some strains were provided by the Caenorhabditis Genetics Center (CGC), which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440).

Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.


  • C. elegans
  • Germline
  • LIP-1 DUSP
  • MPK-1 ERK

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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