PTP1B is an effector of activin signaling and regulates neural specification of embryonic stem cells

Cell Stem Cell. 2013 Dec 5;13(6):706-19. doi: 10.1016/j.stem.2013.09.016. Epub 2013 Oct 17.

Abstract

During embryogenesis, the Activin/Nodal pathway promotes the mesendodermal lineage and inhibits neural fate. The molecular mechanisms underlying this role of the Activin/Nodal pathway are not clear. In this study, we report a role for protein tyrosine phosphatase 1B (PTP1B) in Activin-mediated early fate decisions during ESC differentiation and show that PTP1B acts as an effector of the Activin pathway to specify mesendodermal or neural fate. We found that the Activin/ALK4 pathway directly recruits PTP1B and stimulates its release from the endoplasmic reticulum through ALK4-mediated cleavage. Subsequently, PTP1B suppresses p-ERK1/2 signaling to inhibit neural specification and promote mesendodermal commitment. These findings suggest that a noncanonical Activin signaling pathway functions in lineage specification of mouse and human embryonic stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / chemistry
  • Activin Receptors, Type I / metabolism
  • Activins / metabolism*
  • Amino Acid Sequence
  • Animals
  • Benzamides / pharmacology
  • Cell Differentiation* / drug effects
  • Cell Lineage / drug effects
  • Dioxoles / pharmacology
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / enzymology*
  • Endoderm / cytology
  • Endoderm / drug effects
  • Endoderm / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Mesoderm / cytology
  • Mesoderm / drug effects
  • Mesoderm / metabolism
  • Mice
  • Molecular Sequence Data
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphorylation / drug effects
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / drug effects
  • Pluripotent Stem Cells / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism*
  • Signal Transduction* / drug effects
  • Smad2 Protein / metabolism

Substances

  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • Benzamides
  • Dioxoles
  • Smad2 Protein
  • Activins
  • Extracellular Signal-Regulated MAP Kinases
  • ACVR1B protein, human
  • Activin Receptors, Type I
  • Acvr1b protein, mouse
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1