Author/Authors :
Kang، نويسنده , , Sumin and Dong، نويسنده , , Shaozhong and Gu، نويسنده , , Ting-Lei and Guo، نويسنده , , Ailan and Cohen، نويسنده , , Michael S. and Lonial، نويسنده , , Sagar and Khoury، نويسنده , , Hanna Jean and Fabbro، نويسنده , , Doriano and Gilliland، نويسنده , , D. Gary and Bergsagel، نويسنده , , P. Leif and Taunton، نويسنده , , Jack and Polakiewicz، نويسنده , , Roberto D. and Chen، نويسنده , , Jing، نويسنده ,
Abstract :
Summary
ter understand the signaling properties of oncogenic FGFR3, we performed phospho-proteomics studies to identify potential downstream signaling effectors that are tyrosine phosphorylated in hematopoietic cells expressing constitutively activated leukemogenic FGFR3 mutants. We found that FGFR3 directly tyrosine phosphorylates the serine/threonine kinase p90RSK2 at Y529, which consequently regulates RSK2 activation by facilitating inactive ERK binding to RSK2 that is required for ERK-dependent phosphorylation and activation of RSK2. Moreover, inhibition of RSK2 by siRNA or a specific RSK inhibitor fmk effectively induced apoptosis in FGFR3-expressing human t(4;14)-positive myeloma cells. Our findings suggest that FGFR3 mediates hematopoietic transformation by activating RSK2 in a two-step fashion, promoting both the ERK-RSK2 interaction and subsequent phosphorylation of RSK2 by ERK.
