Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species.

RAS-ERK (extracellular signal-regulated kinase) pathway signals are modulated by scaffold proteins that assemble the components of different kinase tiers into a sequential phosphorylation cascade. In the prevailing model scaffold proteins function as isolated entities, where the flux of phosphorylation events progresses downstream linearly, to achieve ERK phosphorylation. We show that different types of scaffold proteins, specifically KSR1 (kinase suppressor of Ras 1) and IQGAP1 (IQ motif-containing guanosine triphosphatase activating protein 1), can bind to each other, forming a complex whereby phosphorylation reactions occur across both species. MEK (mitogen-activated protein kinase kinase) bound to IQGAP1 can phosphorylate ERK docked at KSR1, a process that we have named trans-phosphorylation. We also reveal that ERK trans-phosphorylation participates in KSR1-regulated adipogenesis, and it also underlies the modest cytotoxicity exhibited by KSR-directed inhibitors. Overall, we identify interactions between scaffold proteins and trans-phosphorylation as an additional level of regulation in the ERK cascade, with broad implications in signaling and the design of scaffold protein-aimed therapeutics

GSK-3ß polymorphism rs6438552 alter transcription and splicing: relationship with depression disease

In this study, we reported the genetic consequences of the expression of SNP rs6438552 glycogen synthase-3ß (GSK-3ß) genotypes in transfected cells and its relationship with depression disease.Máster en Iniciación a la Investigación en Salud Menta

ERK dimerization as a determinant of tumour progression factors

Tesis doctoral en período de exposición públicaBiología Molecular y Biomedicin

Combination of Ruxolitinib with Resminostat exerts antantitumor effects in a chicken embryo metastasis model

Póster presentado en el 34th European Organisation for Research and Treatment of Cancer Symposium (EORTC), celebrado en Barcelona (España) del 26 al 28 de octubre de 2022.Elucidation of molecular targets will improve the clinical management of cutaneous T-cell lymphomas (CTCL). The combination of JAK/HDAC inhibitors exerted beneficial effects in haematological malignancies, presenting promising therapeutic CTCL targets. Our current published data (1) showed that the combination of Resminostat (HDACi) with Ruxolitinib (JAKi) had cytotoxic effect, inhibited proliferation in CTCL cell lines suggesting a strong synergy for both drugs. The drugs¿ combination inhibited phosphorylation of STAT3, Akt, ERK1/2 and JNK in MyLa, while it reduced activation of Akt and JNK in SeAx. It is challenging to explore the effect of JAK/HDACi in tumor formation, angiogenesis and metastasis in CTCL. AIMS: We used a CTCL in vivo chicken embryo model (2), in order to study the effect of Resminostat and/or Ruxolitinib in the possibility of generating primary tumors and studying its metastatic potential in a timely and cost-effective manner offering a number of unique advantages to study the multistep process of tumor cell metastasis. Thus, we generated xenografted tumors derived from MyLa and SeAx cells implanted on top of the chicken c

Combination of resminostat with ruxolitinib exerts antitumor effects in the chick embryo chorioallantoic membrane model for cutaneous T cell lymphoma

The combination of Resminostat (HDACi) and Ruxolitinib (JAKi) exerted cytotoxic effects and inhibited proliferation of CTCL cell lines (MyLa, SeAx) in previously published work. A xenograft tumor formation was produced by implanting the MyLa or SeAx cells on top of the chick embryo chorioallantoic membrane (CAM). The CAM assay protocol was developed to monitor the metastatic properties of CTCL cells and the effects of Resminostat and/or Ruxolitinib in vivo. In the spontaneous CAM assays, Resminostat and Ruxolitinib treatment inhibited the cell proliferation (p < 0.001) of MyLa and SeAx, and induced cell apoptosis (p < 0.005, p < 0.001, respectively). Although monotherapies reduced the size of primary tumors in the metastasis CAM assay, the drug combination exhibited a significant inhibition of primary tumor size (p < 0.0001). Furthermore, the combined treatment inhibited the intravasation of MyLa (p < 0.005) and SeAx cells (p < 0.0001) in the organs, as well as their extravasation to the liver (p < 0.0001) and lung (p < 0.0001). The drug combination also exerted a stronger inhibitory effect in migration (p < 0.0001) rather in invasion (p < 0.005) of both MyLa and SeAx cells. It further reduced p-p38, p-ERK, p-AKT, and p-STAT in MyLa cells, while it decreased p-ERK and p-STAT in SeAx cells in CAM tumors. Our data demonstrated that the CAM assay could be employed as a preclinical in vivo model in CTCL for pharmacological testing. In agreement with previous in vitro data, the combination of Resminostat and Ruxolitinib was shown to exert antitumor effects in CTCL in vivo.This research was funded by a PIE grant (PIE-202020E007) at B.C lab from Consejo Superior de Investigaciones Científicas (CSIC)-MCIU, the Ramon y Cajal Research Program (MCIU, RYC2018-024004-I) and a LA FUNDACIÓ D’ESTUDIS I RECERCA ONCOLÒGICA (FERO) grant (BFERO2021.03)