Research interests
The polymerization of actin monomers into filaments produces mechanical force that sculptures protrusions and invaginations on membranes. Actin dynamics control the remodeling of the plasma membrane and are essential to support cell migration. Not surprisingly, sophisticated mechanisms have evolved to harness the activity of actin nucleators, enzymes required for actin to efficiently form filaments. Actin polymerization by the Arp2/3 complex feeds lamellipodia, veil-like protruding organelles, while the Diaphanous-related Formin mDia2 is implicated in the formation of filopodia, finger-like extensions of the plasma membrane. Interestingly, these two actin nucleators regulate vesicle trafficking, which provides supplies to the leading edge of crawling cells. The Arp2/3 complex and actin also participate in vesicle budding at the plasma membrane and on internal organelles, thus contributing to endocytosis and trafficking.
We tackle the extreme complexity of these networks by focusing on WAVE and N-WASP, two ubiquitous members of the WASP/WAVE-family proteins. These are Nucleation-Promoting Factors that specifically stimulate Arp2/3-complex activity. WAVE- and N-WASP-based core complexes have been shown to spatially and temporally restrict Arp2/3-dependent actin polymerization in a variety of membrane-linked, actin-based processes. However, these core complexes fail to provide a mechanistic explanation for the high versatility of the WASP/WAVE proteins. Our research is revealing that dedicated subunits are required to confer functional specificity to both WAVE and N-WASP core complexes. Moreover, these studies are uncovering new and NPF-independent roles for the WASP/WAVE-family proteins and unexpected links between different classes of actin nucleators. Our investigation exploits state-of-the-art biochemical, cell biological and advanced imaging techniques.
The four main ongoing research lines are:
- Mechanics of formation and function(s) of filopodia in cell migration
- Biochemical characterization of mDia2
- Regulation of the WAVE/Abi1/Nap/Pir (WANP) complex
- Regulation of N-WASP-based complexes
- Actin dynamics in endocytosis
Recent key publications
Beli P, Mascheroni D, Xu D, Innocenti M.
WAVE and Arp2/3 jointly inhibit filopodium formation by entering into a complex with mDia2.
Nat Cell Biol. 2008 May 30.
Innocenti M, Gerboth S, Rottner K, Lai FP, Hertzog M, Stradal TE, Frittoli E, Didry D, Polo S, Disanza A, Benesch S, Di Fiore PP, Carlier MF, Scita G.
Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes.
Nat Cell Biol., 2005 Oct;7(10):969-76. Epub 2005 Sep 11.
Innocenti M, Zucconi A, Disanza A, Frittoli E, Areces LB, Steffen A, Stradal TE, Di Fiore PP, Carlier MF, Scita G.
Abi1 is essential for the formation and activation of a WAVE2 signalling complex.
Nat Cell Biol. 2004 Apr; 6(4):319-27. Epub 2004 Mar 28 8
Steffen A, Rottner K, Ehinger J, Innocenti M, Scita G, Wehland J and Stradal T.
Sra-1 and Nap1 link Rac to actin assembly driving lamellipodia formation.
EMBO J. 2004 Feb 25; 23(4):749-59. Epub 2004 Feb 05
Stradal TE, Rottner K, Disanza A, Confalonieri S, Innocenti M and Scita G.
Regulation of actin dynamics by WASP and WAVE family proteins.
Trends Cell Biol. 2004 Jun;14(6):303-11
Bierne H, Miki H, Innocenti M, Scita G, Gertler FB, Takenawa T, Cossart P.
WASP-related proteins, Abi1 and Ena/VASP are required for Listeria invasion induced by the Met receptor.
J Cell Sci. 2005 Apr 1;118 (Pt 7):1537-47. Epub 2005 Mar 15
Biographic sketch
Metello Innocenti studied Biology at the University of Milan (Italy), where he graduated in 1996. At the end of 1996, he entered the PhD program and continued working on Ras-GRF1, under the supervision of Prof. E. Sturani. He spent the last part of his PhD at the European Institute of Oncology of Milan to investigate on SOS-1. He obtained his PhD in 2000 from the University of Milan (Italy). From 1999 to 2002, he worked as a postdoc in the lab of Prof. P Di Fiore at European Institute of Oncology in Milan. Here, he researched on how Receptor Tyrosine Kinases coordinate the activation of the small GTPases Ras and Rac. Next, he joined the group of Prof. G. Scita at the FIRC Institute of Molecular Oncology in Milan, where he turned his attention on the actin cytoskeleton. At the end of 2005, he moved to Germany and established his independent group at the Frankfurt Medical School. Since May 2009, Metello Innocenti is group leader at the NKI.
Coworkers
Zhen Liu, Postdoc
Magda Galovic, PhD student
Tadamoto Isogai, PhD student
Rob van der Kammen, Technical Staff
Vacancies
Currently, we have openings for one undergraduate internship ('stage') student, a post-doc and a PhD student. For information about the various projects, please contact directly Metello Innocenti (m.innocenti@nki.nl).