Biology subjects

Gesbert, F.

Publications and source records attributed to Gesbert, F..

3 recordsLinked to original sources

bioRxiv2026

Persistence without turnover: RhoG G12E mutant highlights the role of nucleotide cycling in RhoG signaling

Small GTPases of the Ras superfamily act as molecular switches cycling between GDP-bound inactive and GTP-bound active states. Their signaling output depends not only on GTP loading but on continuous nucleotide cycling controlled by GEFs and GAPs. While Gly12 substitutions in Ras typically confer constitutive activation, the effects of equivalent mutations in Rho-family GTPases remain poorly defined. Here, we characterize a ClinVar-reported RhoGG12E variant. Quantitative kinetic studies show that RhoGG12E has strongly impaired intrinsic and GAP-stimulated GTP hydrolysis but it can still be activated by GEFs. Effector binding is preserved in vitro and RhoGG12E accumulates in a GTP-bound state in cells. Yet, RhoGG12E induces enhanced spreading, increased focal adhesions, and reduced collective migration - phenotypes consistent with previously reported consequences of reduced RhoG signaling rather than hyperactivation. These findings indicate that accumulation of the GTP-bound form of small GTPases does not necessarily translate into productive output, supporting a model in which impaired nucleotide cycling compromises RhoG-dependent cellular behaviors.

biochemistry↗

bioRxiv2021

BRN2 is a non-canonical melanoma tumor-suppressor

While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, we show that BRN2 haplo-insufficiency is sufficient to promote melanoma initiation and metastasis, acting as a non-canonical tumor suppressor. Mechanistically, BRN2 directly modulates PTEN expression, and PI3K signaling, to drive tumor initiation and progression. Collectively our results reveal that somatic deletion of one BRN2 allele elicits melanoma initiation and progression. SIGNIFICANCEHere, we report frequent mono-allelic loss of the transcription factor BRN2 in human cutaneous melanoma metastases. We developed a mouse model for Brn2-deficient melanoma based on the most common alterations (BrafV600E and Pten loss) in human melanoma and established the role of Brn2 as a functional regulator of tumor initiation, tumor growth, and the formation of metastases in vivo. Mechanistically, BRN2 loss increases PI3K-signaling through PTEN repression, either via MITF induction or not. Overall, we describe a novel tumor suppressor of high prevalence in human melanoma that regulates several steps of in vivo melanomagenesis through two previously unknown molecular mechanisms.

cancer biology↗

bioRxiv2020

Stabilization of β-catenin promotes melanocyte specification at the expense of the Schwann cell lineage

The canonical Wnt/β-catenin pathway governs a multitude of developmental processes in various cell lineages, including the melanocyte lineage. Indeed, β-catenin regulates Mitf-M transcription, the master regulator of this lineage. The first wave of melanocytes to colonize the skin is directly derived from neural crest cells, while a small number of second wave melanocytes is derived from Schwann-cell precursors (SCPs). We investigated the influence of β-catenin in the development of melanocytes of the first and second waves by generating mice expressing a constitutively active form of β-catenin in cells expressing tyrosinase. Constitutive activation of β-catenin did not affect the development of truncal melanoblasts, but led to a marked hyperpigmentation of the paws. By activating β-catenin at various stages of development (E8.5-E11.5), we showed that the activation of β-catenin in bipotent SCPs favored melanoblast specification at the expense of Schwann cells in the limbs within a specific temporal window. In addition, hyperactivation of the Wnt/β-catenin pathway repressed FoxD3 expression, which is necessary for Schwann cell development, through Mitf-M activation. In conclusion, β-catenin overexpression promotes SCP cell-fate decisions towards the melanocyte lineage.Summary statement Activation of β-catenin in bipotent Schwann-cell precursors during a specific developmental window, induces MITF and represses FoxD3 to promote melanoblast cell fate at the expense of Schwann cells in limbs.View Full Text

developmental biology↗