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Molecular Genetics: Metello Innocenti

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Metello Innocenti, Ph.DGroup Leader

About Metello Innocenti

Research Interest

The polymerization of actin monomers into filaments produces force exploited by cells to move, to remodel their architecture and reshuffle their intracellular components. Since actin cannot self-assemble spontaneously within cells, there are specific enzymes that catalyse the production of new actin filaments consisting of two/three subunits. These enzymes are referred to as actin nucleators, control the formation of protrusions and invaginations on membrane, and are crucial for cell motility. Not surprisingly, sophisticated mechanisms have evolved to harness the activity of actin nucleators.

Our goal is to understand the function and regulation of two important actin nucleators, the Arp2/3 complex and mDia2. The Arp2/3 complex nucleates branched actin filaments powering the formation of lamellipodia, which are veil-shaped cell protrusions required for a mesenchymal-type of migration. mDia2 nucleates linear actin filaments and controls finger-like and non-apoptotic bleb-like protrusions linked to mesenchymal and amoeboid motility, respectively. Interestingly, these two actin nucleators also regulate vesicle trafficking, which provides supplies to the leading edge of crawling cells.

Research line 1: Conditional knockout mouse models to study the roles of Arp2/3 complex
The Arp2/3 complex and its activators are commonly regarded as proto-oncogenes. However, the expression of the Arp2/3 complex is strictly dependent on the tumor type and stage. These observations call for a better evaluation of the contribution lent by the Arp2/3 complex to the onset and progression of cancer. Furthermore, it is emerging that the Arp2/3 complex is also implicated in endocytosis, vesicle trafficking, mitosis and cytokinesis. Since these cellular processes are often deregulated in cancer, we have generated conditional knockout mince to study the roles of the Apr2/3 complex in physiology and cancer.

Research line 2: Functional specification and regulation of the WAVE complex
We previously identified WAVE proteins as key activators of the Arp2/3 complex involved in cell motility. Nevertheless, the role of the WAVE proteins in invasion remains controversial and we hypothesize that tumor-type-dependent regulatory proteins may influence their pro- or anti-metastatic functions. To investigate this we have identified cellular proteins the WAVE interactome and are studying how different binding proteins regulate and/or specify the activity of WAVE.

Research line 3: Regulation and function of mDia2
mDia2 controls the formation of membrane protrusions involved in cell motility and invasion. Interestingly, deregulated mDia2 activity is linked to cancer and other pathologies. However, the actual function of mDia2, the regulation and specification thereof remain unclear. To answer these questions, we have identified the mDia2 interactome and are systematically testing how these interacting proteins affect mDia2-dependent actin polymerization, and filopodium and bleb formation. We aim to assess how inhibition of either type of protrusion impacts on cancer cell migration and invasion.

 
 

Recent publications View All Publications

  • Invadosomes - shaping actin networks to follow mechanical cues.

    Front Biosci (Landmark Ed). 2016 Jun 1;21:1092-117.

    Kedziora KM, Isogai T, Jalink K, Innocenti M.

    Link to Pubmed
  • Proteomic analyses uncover a new function and mode of action for mouse homolog of Diaphanous 2 (mDia2).

    Mol Cell Proteomics. 2015 Apr;14:1064-78

    Isogai T, van der Kammen R, Goerdayal SS, Heck AJ, Altelaar AF, Innocenti M

    Link to Pubmed
 

Contact

  • Office manager

    Marij Degen

  • E-mail

    m.degen_AT_ nki.nl

  • Telephone Number

    +31 (0)20 512 9134

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