Proteomic and Interactome Approaches Reveal PAK4, PHB-2, and 14-3-3η as Targets of Overactivated Cdc42 in Cellular Responses to Genomic Instability.

Cdc42, a member of the Rho GTPase family, is an intracellular signaling protein known for its roles in cytoskeleton rearrangements and, more recently, in apoptosis/senescence triggered by genotoxic stress. In some tumor cells, the overactivation of Cdc42 through the expression of constitutively active mutants (G12V or Q61L), GEF activation, or GAP downregulation functions as an antiproliferative or pro-aging mechanism. In this study, human cell lines with different P53 protein profiles were exposed to UV radiation, and the interactions between Cdc42 and proteins that are putatively involved in the DNA damage response and repair mechanisms were screened.

Network analysis of DUSP12 partners in the nucleus under genotoxic stress.

Dual Specificity Phosphatase 12 is a member of the Atypical DUSP Protein Tyrosine Phosphatase family, meaning that it does not contain typical MAP kinase targeting motifs, while being able to dephosphorylate tyrosine and serine/threonine residues. DUSP12 contains, apart from its catalytic domain, a zinc finger domain, making it one of the largest DUSPs, which displays strong nuclear expression in several tissues. In this work we identified nuclear targets of DUSP12 in two different cancer cell lines (A549 and MCF-7), challenging them with genotoxic stimuli to observe the effect on the networks and to link existing information about DUSP12 functions to the data obtained though mass spectrometry.

Revisiting the roles of VHR/DUSP3 phosphatase in human diseases.

Protein tyrosine phosphatases have long been considered key regulators of biological processes and are therefore implicated in the origins of various human diseases. Heterozygosity, mutations, deletions, and the complete loss of some of these enzymes have been reported to cause neurodegenerative diseases, autoimmune syndromes, genetic disorders, metabolic diseases, cancers, and many other physiological imbalances. Vaccinia H1-related phosphatase, also known as dual-specificity phosphatase 3, is a protein tyrosine phosphatase enzyme that regulates the phosphorylation of the mitogen-activated protein kinase signaling pathway, a central mediator of a diversity of biological responses.

DUSP3/VHR: A Druggable Dual Phosphatase for Human Diseases.

Protein tyrosine kinases (PTK), discovered in the 1970s, have been considered master regulators of biological processes with high clinical significance as targets for human diseases. Their actions are countered by protein tyrosine phosphatases (PTP), enzymes yet underrepresented as drug targets because of the high homology of their catalytic domains and high charge of their catalytic pocket. This scenario is still worse for some PTP subclasses, for example, for the atypical dual-specificity phosphatases (ADUSPs), whose biological functions are not even completely known.

Measuring the Contributions of the Rho Pathway to the DNA Damage Response in Tumor Epithelial Cells.

Actin polymerization, actomyosin ring contraction, and stress fiber formation are examples of relevant actions of the RhoA/B/C pathway as GTPases that regulate the cytoskeleton. However, open questions that remain to be addressed are whether this pathway and/or downstream components protect against or facilitate the formation of DNA double-strand breaks, the most lethal form of DNA damage in cells. Genotoxic drugs are radiomimetic and/or chemotherapeutic agents that are currently used for cancer treatments and are associated with specific methodologies; thus, these compounds should represent good tools to answer these questions.