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CD44 is associated with a high risk of metastasis, recurrence, and drug resistance in various cancers. Here we report that platelet endothelial aggregation receptor 1 (PEAR1) is a CD44 chaperone protein that protected CD44 from endocytosis-mediated degradation and enhances cleavage of the CD44 intracellular domain (CD44-ICD). Furthermore, we found that lysyl oxidase-like protein 2 (LOXL2), an endogenous ligand of PEAR1, bound to the PEAR1-EMI domain and facilitated the interaction between PEAR1 and CD44 by inducing PEAR1 Ser891 phosphorylation in a manner that was independent of its enzyme activity. Levels of PEAR1 protein and PEAR1 phosphorylation at Ser891 were increased in patients with triple-negative breast cancer (TNBC), were positively correlated with expression of LOXL2 and CD44, and were negatively correlated with overall survival. The level of PEAR1 Ser891 phosphorylation was identified as the best independent prognostic factor in TNBC patients. The prognostic efficacy of the combination of PEAR1 phosphorylation at Ser891 and CD44 expression was superior to that of PEAR1 phosphorylation at Ser891 alone. Blocking the interaction between LOXL2 and PEAR1 with monoclonal antibodies significantly inhibited TNBC metastasis, representing a promising therapeutic strategy for TNBC., Introduction Breast cancer is the most prevalent malignancy in women, and its incidence is increasing (1). Of particular concern is triple-negative breast cancer (TNBC), which is an exceptionally aggressive and [...]

Smoothelin-like 1 (SMTNL1) modulates the contractile performance of smooth muscle and thus has a key role in vascular homeostasis. Elevated vascular tone, recognized as a contributor to the development of progressive cardiac dysfunction, was previously found with SMTNL1 deletion. In this study, we assessed cardiac morphology and function of male and female, wildtype ([Smtnl1.sup.1+/+]) and global SMTNL1 knockout ([Smtnl1.sup.1-/-]) mice at 10 weeks of age. Gross dissection revealed distinct cardiac morphology only in males; [Smtnl1.sup.-/-] hearts were significantly smaller than [Smtnl1.sup.+/+], but the left ventricle (LV) proportion of heart mass was greater. Male [Smtnl1.sup.-/-] mice also displayed increased ejection fraction and fractional shortening, as well as elevated aortic and pulmonary flow velocities. The impact of cardiac stress with pressure overload by transverse aortic constriction (TAC) was examined in male mice. With TAC banding, systolic function was preserved, but the LV filling pressure was selectively elevated due to relaxation impairment. [Smtnl1.sup.-/-] mice displayed higher early/passive filling velocity of LV/early mitral annulus velocity ratio (E/E' ratio) and myocardial performance index along with a prolonged isovolumetric relaxation time. Taken together, the findings support a novel, sex-dimorphic role for SMTNL1 in modulating cardiac structure and function of mice. Key words: SMTNL1, sex dimorphism, peripheral vascular resistance, transverse aortic constriction, pressure-volume relationship SMTNL1 (pour << smoothelin-like 1 >>) participe a la modulation de la performance contractile du muscle lisse et joue donc un role cle dans l'homeostasie vasculaire. On a precedemment montre avec la deletion de SMTNL1 une augmentation du tonus vasculaire, reconnue comme pouvant contribuer a l'evolution d'un dysfonctionnement progressif du coeur. Dans cette etude, nous avons evalue la morphologie et le fonctionnement du coeur chez des souris males et femelles de type sauvage ([Smtnl1.sup.+/+]) et avec << knockout >> de SMTNL1 ([Smtnl1.sup.-/-]) agees de 10 semaines. La dissection macroscopique a revele la presence d'une morphologie cardiaque distincte uniquement chez les males; les coeurs [Smtnl1.sup.-/-] etaient nettement plus petits que chez les [Smtnl1.sup.+/+], mais la proportion de la masse du VG sur celle de l'ensemble du coeur etait plus elevee. Les souris [Smtnl1.sup.-/-] males presentaient aussi une augmentation de la fraction d'ejection et de la fraction de raccourcissement, de meme que des vitesses des flux aortique et pulmonaire. Nous avons examine l'incidence du stress cardiaque sur la surcharge de pression par la constriction aortique transverse (TAC) chez les souris males. Avec le cintrage de la TAC, la fonction systolique etait preservee, mais le remplissage du VG augmentait de selectivement en raison de la perturbation de la relaxation. Les souris [Smtnl1.sup.-/-] ont presente un ratio E/E' et un indice de la performance cardiaque plus eleves, avec une prolongation de la duree de la relaxation isovolumetrique. Dans leur ensemble, les resultats viennent appuyer un nouveau role de SMTNL1 marque par le dimorphisme sexuel dans la modulation de la structure et du fonctionnement du coeur chez la souris. [Traduit par la Redaction] Mots-cles : SMTNL1, dimorphisme sexuel, resistance vasculaire peripherique, constriction aortique transverse, lien entre la pression et le volume, Introduction Smoothelin-like 1 (SMTNL1; originally termed calponin homology-associated smooth muscle protein, CHASM) was first identified during proteomic studies of smooth muscle (Borman et al. 2004; Murali and MacDonald 2018). Unique [...]

Development of tau-based therapies for Alzheimer's disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer's disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-[beta] as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-[beta] and neurodegeneration, and may facilitate clinical trials of tau-based treatments. Site-specific hyperphosphorylations of tau in the cerebrospinal fluid change with disease course, and correlate with pathology and cognitive decline in dominantly inherited Alzheimer's disease., Author(s): Nicolas R. Barthélemy [sup.1] , Yan Li [sup.1] [sup.2] , Nelly Joseph-Mathurin [sup.3] , Brian A. Gordon [sup.3] , Jason Hassenstab [sup.1] , Tammie. L. S. Benzinger [sup.3] , [...]

Insulin resistance is present in one-quarter of the general population, predisposing these people to a wide range of diseases. Our aim was to identify cell-intrinsic determinants of insulin resistance in this population using induced pluripotent stem cell-derived (iPSC-derived) myoblasts (iMyos). We found that these cells exhibited a large network of altered protein phosphorylation in vitro. Integrating these data with data from type 2 diabetic iMyos revealed critical sites of conserved altered phosphorylation in IRS-1, AKT, mTOR, and TBC1D1 in addition to changes in protein phosphorylation involved in Rho/ Rac signaling, chromatin organization, and RNA processing. There were also striking differences in the phosphoproteome in cells from men versus women. These sex-specific and insulin-resistance defects were linked to functional differences in downstream actions. Thus, there are cell-autonomous signaling alterations associated with insulin resistance within the general population and important differences between men and women, many of which also occur in diabetes, that contribute to differences in physiology and disease., Introduction Insulin resistance is a major risk factor in the development of metabolic syndrome, type 2 diabetes (T2D), and cardiovascular disease (1-4). Indeed, the cardiometabolic syndrome currently affects 20% to [...]

Skeletal muscle preeminently determines whole-body glycemla. However, the molecular basis and inheritable influence that drive the progression of insulin resistance to type 2 diabetes remain debated. In this issue of the JCI, Haider and Lebastchi report on their use of induced pluripotent stem cell-derived (iPSC-derived) myoblasts (iMyos) to uncover multiple phosphoproteomic changes that carried over from the human to the cell-culture system. In this system devoid of in vivo influences, the researchers annotated changes between the sexes and between the most and least insulin-sensitive quintiles of a healthy population (defined by steady-state blood glucose levels). Many phosphoproteomic differences were detected in the absence of insulin, revealing that changes in the basal landscape of cells determine the efficiency of insulin action. Basal and insulin-dependent deficiencies of iPSCs and iMyos likely involve genetic and epigenetic determinants that modulate insulin sensitivity., Deconstruct to conquer insulin resistance Skeletal muscle glucose uptake is crucial for the maintenance of glycemia and for providing a carbon source to this highly energy-demanding tissue (1). Muscle fibers [...]

Huntington's disease (HD) is a progressive, adult-onset neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the N-terminal region of the protein huntingtin (HTT). There are no cures or disease-modifying therapies for HD. HTT has a highly conserved Akt phosphorylation site at serine 421, and prior work in HD models found that phosphorylation at S421 (S421-P) diminishes the toxicity of mutant HTT (mHTT) fragments in neuronal cultures. However, whether S421-P affects the toxicity of mHTT in vivo remains unknown. In this work, we used murine models to investigate the role of S421-P in HTT-induced neurodegeneration. Specifically, we mutated the human mHTT gene within a BAC to express either an aspartic acid or an alanine at position 421, mimicking tonic phosphorylation (mHTT-S421D mice) or preventing phosphorylation (mHTT-S421A mice), respectively. Mimicking HTT phosphorylation strongly ameliorated mHTT-induced behavioral dysfunction and striatal neurodegeneration, whereas neuronal dysfunction persisted when S421 phosphorylation was blocked. We found that S421 phosphorylation mitigates neurodegeneration by increasing proteasome-dependent turnover of mHTT and reducing the presence of a toxic mHTT conformer. These data indicate that S421 is a potent modifier of mHTT toxicity and offer in vivo validation for S421 as a therapeutic target in HD., Introduction Huntington's disease (HD) is a devastating neurodegenerative disorder with no cure or disease-altering treatment. HD patients present clinically with any combination of abnormal movements, dementia, and affective changes and [...]