Molecular bases of actin cytoskeleton reorganization in neuritogenesis, cell motility, tumor generation and invasiveness

IAnton

 

Inés Antón

Group Leader

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Research summary

Essential processes such as neuronal morphogenesis, cell motility and tissue invasion rely on the spatial and temporal regulation of actin dynamics and therefore, their deregulation is at the root of severe pathologies. Actin reorganization is controlled by nucleation-promoting factors like neural Wiskott-Aldrich syndrome protein (N-WASP) and cortactin, and associated proteins that regulate their activity such as WIP (WASP-interacting protein), a ubiquitously distributed protein that stabilizes actin filaments. Our goal is to define the role of WIP- and WASP-family proteins in actin dynamics within a variety of cellular processes in fibroblasts, dendritic cells (DC), neurons and astrocytes.

 

Publications

Escoll M, Gargini RA, Cuadrado A, IM Anton, Wandosell F. Mutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ. Oncogene 2017; 36:3515-3527

Gargini RA, Escoll M, García E, García-Escudero R, Wandosell F, IM Anton. WIP drives tumor progression to promote YAP/TAZ-dependent autonomous cell growth. Cell Reports 2016; 17 (8):1962-1977

García E, Ragazzini, C, Yu X, Cuesta-García E, Zech T, Sarrio D, Machesky LM, IM Anton. WIP and WICH/WIRE co-ordinately control invadopodium formation and maturation in human breast cancer cell invasion. Scientific Reports 2016; 6:23590

Franco-Villanueva A, Fernández-López E, Gabandé-Rodríguez E, Bañón-Rodríguez I, Esteban JA, Anton IM, MD Ledesma. WIP modulates dendritic spine actin cytoskeleton by transcriptional control of lipid metabolic enzymes. Human Mol Genetics 2014; 23:4383-4395

García E, Machesky LM, Jones GE, IM Anton. WIP is necessary for matrix invasion by breast cancer cells. Eur J Cell Biol 2014; 93:413- 423

 

Figure2Our aim is to determine the mechanisms that regulate cytoskeletal dynamics in essential actin-mediated cell functions such as migration, invasion, and neuronal differentiation. We study actin-binding proteins such as (N)WASP (neural Wiskott-Aldrich syndrome protein), WIP (WASP-interacting protein) and WIRE (WIP-related) to understand the molecular mechanisms that underlie inflammation-mediated conditions, tumour invasion and neurological diseases.

Using animal models and recombinant lentivirus, we identified an essential role for WIP in persistence during amoeboid (B lymphocyte) and mesenchymal (fibroblast) migration as well as in fibroblast chemotaxis. Advanced imaging techniques and biochemical approaches allowed us to elucidate the role of WIP in the formation of actin-rich invasive structures, podosomes and invadopodia. We determined how Btk-mediated tyrosine phosphorylation of WIP triggers WASP release from the WIP-WASP complex to regulate podosome lifetime. Using 2D and 3D culture systems, we demonstrated that WIP is necessary for invadopodium formation and matrix degradation by basal breast cancer cells. Finally, we identified WIP as a component of neuronal synapses whose absence increases dendritic spine size and filamentous actin levels in a RhoA/ROCK/profilinIIa-dependent manner. These effects depend on the reduction of membrane sphingomyelin due to transcriptional upregulation of neutral sphingomyelinase through active RhoA; this enhances RhoA binding to the membrane in steady state but prevents changes in response to stimulus. Sphingomyelinase inhibition or sphingomyelin addition reverses the RhoA-dependent increase in filamentous actin, as well as functional anomalies in WIP-deficient synapses. Our findings characterise WIP as a link between membrane lipid composition and actin cytoskeleton at dendritic spines. They also contribute to explain cognitive deficits shared by individuals bearing mutations in the region assigned to the gene that encodes WIP.

Our goal is to understand the molecular basis of the mechanism that regulates actin polymerisation, a process that underlies numerous essential cell functions whose deregulation leads to serious human diseases. We thus hope to provide new diagnostic, prognostic and/or therapeutic tools for neurological disorders, inflammation-mediated affections, tumour initiation and metastasis.

 

Figure1BisCIA Flag WIRE 5

 

grupoAnton

 

Name
Position
Contact
Inés Antón Principal investigator
Ricardo Gargini Postdoctoral scientist
Esther García Predoctoral scientist

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