Proteomic analyses uncover a new function and mode of action for mouse homolog of diaphanous 2 (mDia2)

Tadamoto Isogai, Rob Van Der Kammen, Soenita S. Goerdayal, Albert J. R. Heck, A. F. Maarten Altelaar, Metello Innocenti*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

mDia2 is an auto-inhibited Formin influencing actin dynamics upon conversion to the active conformation. mDia2 regulates actin-based protrusions and cell invasion, cell differentiation, vesicle trafficking, and cytokinesis. However, whether mDia2 has additional functions and how its action is functionally specified remain unknown. Here we draw the interactome of auto-inhibited and constitutively active mDia2 to address these issues. We embed mDia2 in protein networks accounting for its attributed functions and unexpectedly link it to the Ubiquitin Proteasome System. Taking FBXO3 as a test case, we show that mDia2 binds FBXO3 and p53, and regulates p53 transcriptional activity in an actin-nucleation-independent and conformation-insensitive manner. Increased mDia2 and FBXO3 levels elevate p53 activity and expression thereby sensitizing cells to p53-dependent apoptosis, whereas their decrease produces opposite effects. Thus, we discover a new role of mDia2 in p53 regulation suggesting that the closed conformation is biologically active and an FBXO3-based mechanism to functionally specify mDia2's activity.
Original languageEnglish
Pages (from-to)1064-1078
Number of pages15
JournalMolecular & Cellular Proteomics
Volume14
Issue number4
DOIs
Publication statusPublished - 1 Apr 2015

Keywords

  • caspase 3
  • caspase 7
  • mouse homolog of diaphanous 2
  • protein p53
  • regulator protein
  • unclassified drug
  • actin filament
  • apoptosis
  • article
  • autophagy
  • cell migration
  • cell motility
  • cell polarity
  • conformational transition
  • down regulation
  • gain of function mutation
  • loss of function mutation
  • priority journal
  • protein analysis
  • protein binding
  • protein expression
  • protein function
  • protein protein interaction
  • proteomics
  • transcription regulation
  • ubiquitination

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