The growth of endochondral bones relies on the coordinated proliferation and hypertrophy of chondrocytes. This process is governed by several transcription factors and epigenetic modifiers that regulate distinct steps, likely by assembling into larger complexes that bind to DNA. The transcription factor Trps1 has previously been shown to interact with the activator form of Gli3 (Gli3A) and the histone deacetylase Hdac4, two critical regulators of chondrocytes proliferation and differentiation. Here, we show that the interaction with Trps1 increases the abundance of both proteins and promotes their nuclear localization. We further demonstrate that Trps1 acts independently of PKA and PP2A activity, which have been reported to regulate the nuclear localization and activity of Gli3A and Hdac4. Trps1 and Gli3A complexes were predominantly found in proliferating chondrocytes, whereas Trps1 and Hdac4 interactions occurred more frequently in prehypertrophic chondrocytes, suggesting differentiation-specific changes in protein interactions. These findings reveal the regulation of protein abundance and nuclear availability as a novel mechanism by which Trps1 controls gene expression during chondrocyte differentiation.

Lung adenocarcinoma (LUAD) the predominant subtype of lung cancer, is characterized by rapid tumor growth, local invasion, and distant metastasis. Since dysregulated expression of synaptotagmin (SYT) proteins have been implicated in the development and progression of LUAD, the specific role and mechanisms of SYT15B in LUAD remain unclear. This study demonstrates that elevated SYT15B expression drives malignant progression and predicts poor prognosis in LUAD, as evidenced by integrated clinical sample, in vitro, and in vivo analyses. We identify a novel molecular mechanism whereby SYT15B interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1), leading to activation of the MAPK signalling pathway and subsequent promotion of aggressive tumor phenotypes. Disruption of the SYT15B-IQGAP1 interaction through IQGAP1 knockdown attenuated MAPK signalling pathway activation and reversed the oncogenic phenotype induced by SYT15B. Notably, specific inhibition of intracellular calcium with BAPTA can also attenuates SYT15B-IQGAP1 complex formation, abrogates MAPK signalling activation, and reverses SYT15B-mediated oncogenic effects. These findings establish the calcium-dependent SYT15B/IQGAP1/MAPK axis as a potential therapeutic and prognostic biomarker in LUAD.

Regulator of G protein signaling 10 (RGS10) is a GTPase activating protein, selective for Gαi, that has been proposed to play a role in suppressing microglia-driven neuroinflammation. RGS10 expression in microglia is suppressed by inflammatory stimuli and aging, and loss of RGS10 is associated with increased cytokine expression and neurodegeneration. Conversely, RGS10 overexpression provides protection against inflammatory stimuli in rodent models, however the mechanisms by which RGS10 exerts this protective effect are unknown. To understand the neuroprotective functions of RGS10 in microglia, we completed RNA-Seq analysis in the murine microglial cell line BV-2 with intact (BV-2WT) and absent (RGS10-/-) RGS10 expression, with or without interferon-γ (IFNγ)-stimulation. We identified genes whose expression were altered as a result of RGS10 loss, IFNγ stimulation, or both. As expected, RGS10 loss resulted in changes in processes such as GPCR signaling and synaptic signaling. However, this analysis also revealed that processes such as cell migration and adhesion were altered in RGS10-/- cells, under both basal and IFNγ-stimulated conditions. Key cell adhesion genes such as Mmp9 and Thbs1 were downregulated in RGS10-/- cells regardless of stimuli. Experimentally, loss of RGS10 increased BV-2 cell migration, and IFNγ stimulation led to a reduction in migration of both BV-2WT and RGS10-/- cells. The effect of RGS10 on migration could only partially be blocked by the Gαi inhibitor Pertussis toxin (PTX), suggesting involvement of both G protein-dependent and -independent mechanisms. Altogether, these results suggest a novel role for RGS10 in reducing microglial migration through regulation of cell adhesion genes.