A crucial role for the phosphorylation of STRAP at Ser(188) by MPK38 in STRAP-dependent cell death through ASK1, TGF-β, p53, and PI3K/PDK1 signaling pathways

Cell Cycle. 2014;13(21):3357-74. doi: 10.4161/15384101.2014.952165.

Abstract

Serine-threonine kinase receptor-associated protein (STRAP) is a TGF-β receptor-interacting protein that participates in the regulation of cell proliferation and cell death in response to various stresses. Here, we demonstrate that STRAP phosphorylation plays an important role in determining the pro- or anti-apoptotic function of STRAP. Murine protein serine/threonine kinase 38 (MPK38) phosphorylates STRAP at Ser(188) via direct interaction. Complex formation between STRAP and MPK38 is mediated by Cys(152) and Cys(270) of STRAP and Cys(339) and Cys(377) of MPK38, suggesting the redox dependency of this interaction. MPK38-mediated STRAP Ser(188) phosphorylation contributes to the pro-apoptotic function of STRAP by modulating key steps in STRAP-dependent ASK1, TGF-β, p53, and PI3K/PDK1 signaling pathways. Moreover, knockdown of endogenous MPK38 using an inducible MPK38 shRNA system and in vivo activation of MPK38 by treatment of HEK293 and STRAP-null MEF cells with 1-chloro-2,4-dinitrobenzene (DNCB), a specific inhibitor of Trx reductase, provide evidence that STRAP Ser(188) phosphorylation plays a key role in STRAP-dependent cell death. Adenoviral delivery of MPK38 in mice also demonstrates that STRAP Ser(188) phosphorylation in the liver is tightly associated with cell death and proliferation through ASK1, TGF-β, p53, and PI3K/PDK1 pathways, resulting in apoptotic cell death.

Keywords: ASK1; ASK1, apoptosis signal-regulating kinase 1; MPK38, murine protein serine/threonine kinase 38; MPK38/MELK; PDK1, 3-phosphoinositide-dependent protein kinase-1; PI3K, phosphoinositide 3-kinase; PI3K/PDK1; STRAP; STRAP, serine-threonine kinase receptor-associated protein; TGF-β; ZPR9, zinc finger-like protein 9; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis* / drug effects
  • Cell Line
  • Dinitrochlorobenzene / pharmacology
  • HEK293 Cells
  • Humans
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • RNA, Small Interfering / metabolism
  • RNA-Binding Proteins
  • Serine / chemistry
  • Signal Transduction*
  • Transforming Growth Factor beta / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Dinitrochlorobenzene
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • STRAP protein, mouse
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • Serine
  • Melk protein, mouse
  • Protein-Serine-Threonine Kinases
  • MAP Kinase Kinase Kinase 5
  • Map3k5 protein, mouse