Biology subjects

Rubio, I.

Publications and source records attributed to Rubio, I..

2 recordsLinked to original sources

bioRxiv2025

The microcephaly-associated protein YIPF5 differentially regulates ER-export

YIPF5 is a small ER-membrane protein implicated in ER-Golgi transport. Mutations in YIPF5 cause MEDS2 (microcephaly with simplified gyral pattern, epilepsy, and neonatal diabetes syndrome), a fatal disorder manifesting in early childhood. We demonstrate that YIPF5 is involved in ER export of a subset of proteins, including cargoes of the ER-export receptor SURF4, with which it directly interacts. In YIPF5 knockout cells, we observe a shift in the cell surface and secretome composition, marked by reduced neuronal adhesion molecules and increased secretion of ER chaperones influencing cell migration. YIPF5 depletion enhances cell migration in a wound-healing assay and alters SURF4 localization, causing elongated ERGIC53- and Rab1-positive tubules from COPII-labeled ER exit sites. Kinetic analysis suggests that YIPF5 negatively regulates SURF4-mediated ER export. In utero knockdown of Yipf5 in embryonic mouse brains induces premature neuronal migration and abnormal neuronal morphology. These findings suggest that YIPF5 and SURF4 coordinate ER export, and disruption may underlie cortical development defects leading to microcephaly.

cell biology↗

bioRxiv2023

A critical role for PLCG1 in RAS activation by BCR-ABL1 and FLT3-ITD

Myeloid leukemias are frequently associated with pathologically activating mutations in tyrosine kinases [BCR-ABL1 in chronic myeloid leukemia (CML); FLT3 juxtamembrane internal tandem duplication (ITD) mutations, FLT3 and KIT activation loop mutations in acute myeloid leukemia (AML)]. Mutations in these kinases activate RAS, which initiates multiple downstream signaling pathways that regulate cell proliferation, differentiation, and apoptosis. The mechanisms whereby RAS is activated by these kinases is incompletely understood, and a better understanding of the molecular mediators involved in RAS activation may uncover new therapeutic strategies. Here we identify a biologically and therapeutically important novel mechanism whereby BCR-ABL1 and FLT3-ITD activate the critical downstream effector RAS in part through phospholipase C gamma-1 (PLCG1). PLCG1 knockout decreases proliferation of CML and FLT3-ITD-expressing AML cells, reduces RAS nucleotide exchange factor activity, and increases sensitivity of CML cells to BCR-ABL1 tyrosine kinase inhibitors (TKIs). Collectively, these studies suggest that PLCG1 inhibition may augment clinical responses to BCR-ABL1 and FLT3 TKIs in CML and AML.

cancer biology↗