HNRNPA2B1 Promotes the Progression of Multiple Myeloma via Endoplasmic Reticulum Stress and Autophagy Mediated by CK2 Kinase

In our previous study, we discovered that HNRNPA2B1 exhibited oncogenic activity in multiple myeloma (MM) and protein phosphorylation modifications could play a crucial role in this progression. The aim of this study is to explore the phosphorylation cascades regulated by HNRNPA2B1 in MM and to pinpoint the principal kinase target while clarifying the underlying mechanism. Therefore, quantitative proteome and phosphoproteome analyses were employed to investigate the protein phosphorylation cascades and kinase enrichment analysis was used to predict kinase activity and identify the key kinase target. As a result, in HNRNPA2B1 knockdown myeloma cells, 22 differential kinases and 56 phosphorylation sites were identified and a kinase regulatory network comprising 154 kinase-substrate interactions was constructed. Key kinase targets, CK2 and MAP2K, were identified and validated. The CK2 kinase inhibitor TBB markedly reduced the proliferation of HNRNPA2B1-overexpression MM cells, enhanced cell apoptosis, and triggered ER stress and autophagy activation. In conclusion, this investigation provides a comprehensive overview of the protein phosphorylation cascades regulated by HNRNPA2B1 in MM, identifying CK2 as a crucial kinase target. Inhibiting CK2 kinase not only affects MM cell proliferation and apoptosis but also induces ER stress and autophagy, providing novel insights into MM pathogenesis.