Biology subjects

Baccarini, M.

Publications and source records attributed to Baccarini, M..

6 recordsLinked to original sources

bioRxiv2026

RAStoERK: a reference interaction atlas for insights into signaling and disease

The RAS/RAF/MEK/ERK pathway has been extensively studied for its roles in physiology and disease, yet a systems-level view of its interplay with the broader cellular context is lacking, limiting insight into paralog-specific roles, mutation-driven rewiring, and cross-pathway integration. To address this, we simultaneously mapped the interactomes of all pathway components and their activating and inactivating mutations, identifying 2,500 high-confidence interactors, 88% of which previously unreported, and generating a high-confidence, comprehensive reference map of the pathway in resting and activated states. The pathway behaves like a "molecular organism" that connects to other signaling complexes, operates from distinct subcellular sites, and integrates into networks relevant to physiology and disease. Dataset exploration uncovered paralog- and mutation-specific interaction signatures and pathway-level crosstalk, including previously unknown connections to mRNA metabolism and WNT signaling. The interactomes available at RAStoERK.univie.ac.at provide a foundational community resource for unbiased discovery, targeted mechanistic studies, and potential therapeutic exploration. HighlightsO_LIHigh-resolution interactome map of the RAS to ERK pathway in resting and active states C_LIO_LIState-dependent pathway-level interactions with signaling and functional modules C_LIO_LIMutation-driven interactome rewiring and integration into pathophysiological networks C_LIO_LIA resource to discover pathway crosstalk, disease links, and actionable interventions C_LI

molecular biology↗

bioRxiv2023

Pre-mRNA fate decision safeguards the fidelity of the inflammatory response

The fidelity of immune responses depends on a timely controlled and selective mRNA degradation that is largely driven by RNA-binding proteins (RBPs)[1, 2]. It remains unclear whether the selection of an individual mRNA molecule for degradation is governed by stochastic or directed processes. Here, we show that tristetraprolin (TTP, also known as ZFP36), an essential anti-inflammatory RBP[3], destabilizes target mRNAs via a hierarchical molecular assembly. The formation of the assembly strictly relies on the interaction of TTP with RNA. The TTP homolog ZFP36L1 exhibits similar requirements, indicating a broader relevance of this regulatory program. Unexpectedly, the assembly of the cytoplasmic mRNA-destabilization complex is licensed in the nucleus by TTP binding to pre-mRNA, while mature cytoplasmic mRNA does not constitute a de novo TTP target. Hence, the fate of an inflammation-induced mRNA is decided concomitantly with its synthesis. This decision mechanism prevents the translation of superfluous and potentially harmful inflammation mediators, ensuring an efficient cessation of the immune response, irrespective of transcriptional activity.

molecular biology↗

bioRxiv2023

Interplay between PLEKHG3-regulated actin dynamics and lysosomal trafficking in cell motility

Lysosomes are dynamic organelles regulating metabolic signaling by recruiting cytosolic molecules to protein platforms on their limiting membrane. We used proximity labeling to define interactors and vicinal proteins of LAMTOR3, a component of the Ragulator scaffold that controls mTORC1 signaling and lysosome positioning. The screen has yielded several previously unappreciated interactors, including an actin remodeling network. Here, we characterize the RhoGEF PLEKHG3 as a LAMTOR3 vicinal protein colocalizing with peripheral lysosomes and cortical F-actin at focal adhesion sites. Forced peripheral dispersion of lysosomes drives PLEKHG3 accumulation at focal adhesions and decreases protrusive activity in both wild-type and PLEKHG3-deficient cells. Thus, lysosome positioning governs both PLEKHG3 localization and protrusive activity, yet the protrusion changes can occur independently of PLEKHG3.

cell biology↗

bioRxiv2021

amica: an interactive and user-friendly web-platform for the analysis of proteomics data

SummaryQuantitative proteomics has become an increasingly prominent tool in the study of life sciences. A substantial hurdle for many biologists are, however, the intricacies involved in the associated high throughput data analysis. In order to facilitate this task for users with limited background knowledge, we have developed amica, a freely available open-source web-based software that accepts proteomic input files from different sources and provides quality control, differential expression, biological network and over-representation analysis on the basis of minimal user input. Scientists can use amica interactively to compare proteins across multiple groups, create customized output graphics, and ultimately export the results in a tab-separated format that can be shared with collaborators. Availability and ImplementationThe code for the application, input data and documentation can be accessed online at https://github.com/tbaccata/amica and is also incorporated in the web application. A freely available version of amica is available at https://bioapps.maxperutzlabs.ac.at/app/amica.

bioinformatics↗

bioRxiv2018

The Dimer-dependent Catalytic Activity of RAF Family Kinases Is Revealed Through Characterizing Their Oncogenic Mutants

Although extensively studied for three decades, the molecular mechanisms that regulate the RAF/MEK/ERK kinase cascade remain ambiguous. Recent studies identified the dimerization of RAF as a key event in the activation of this cascade. Here, we show that in-frame deletions in the {beta}3-C loop activate ARAF as well as BRAF and other oncogenic kinases by enforcing homodimerization. By characterizing these RAF mutants, we find that ARAF has less allosteric and catalytic activity than the other two RAF isoforms, which arises from its non-canonical APE motif. Further, these RAF mutants exhibit a strong oncogenic potential, and a differential inhibitor resistance that correlates with their dimer affinity. Using these unique mutants, we demonstrate that active RAFs, including the BRAF(V600E) mutant, phosphorylate MEK in a dimer-dependent manner. This study characterizes a special category of oncogenic kinase mutations, and elucidates the molecular basis that underlies the differential ability of RAF isoforms to stimulate MEK-ERK pathway. Further, this study reveals a unique catalytic feature of RAF family kinases that can be exploited to control their activities for cancer therapies.

cancer biology↗

bioRxiv2017

The Activation of MEK1 by Enhanced Homodimerization Drives Tumorigenesis

Hyperactive RAS/RAF/MEK/ERK signaling has a well-defined role in cancer biology. Aberrant pathway activation occurs mostly upstream of MEK; however, MEK mutations are prevalent in some cancer subsets. Here we show that cancer-related MEK mutants can be classified as those activated by relieving the inhibitory role of helix A, and those with in-frame deletions of {beta}3-C loop, which exhibit differential resistance to MEK inhibitors in vitro and in vivo. The {beta}3-C loop deletions activate MEK1 through enhancing homodimerization that can drive intradimer cross-phosphorylation of activation loop. Further, we demonstrate that MEK1 dimerization is required both for its activation by RAF and for its catalytic activity towards ERK. Our study identifies a novel group of MEK mutants, illustrates some key steps in RAF/MEK/ERK activation, and has important implications for the design of therapies targeting hyperactive RAS/RAF/MEK/ERK signaling in cancers.

cancer biology↗