A PREVIOUSLY UNKNOWN UNIQUE CHALLENGE FOR INHIBITORS OF SYK ATP-BINDING SITE: ROLE OF SYK AS A CELL CYCLE CHECKPOINT REGULATOR.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 25506060.
- Also identified by PMC identifier 4259291.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The identification of SYK as a molecular target in B-lineage leukemia/lymphoma cells prompted the development of SYK inhibitors as a new class of anti-cancer drug candidates. Here we report that induction of the SYK gene expression in human cells causes a significant down-regulation of evolutionarily conserved genes associated with mitosis and cell cycle progression providing unprecedented evidence that SYK is a master regulator of cell cycle regulatory checkpoint genes in human cells. We further show that SYK regulates the G<sub>2</sub> checkpoint by physically associating with and inhibiting the dual-specificity phosphatase CDC25C via phosporylation of its S216 residue. SYK depletion by RNA interference or treatment with the chemical SYK inhibitor prevented nocodazole-treated human cell lines from activating the G<sub>2</sub> checkpoint via CDC25C S216-phoshorylation and resulted in polyploidy. Our study provides genetic and biochemical evidence that spleen tyrosine kinase (SYK) has a unique role in the activation of the G<sub>2</sub> checkpoint in both nonlymphohematopoietic and B-lineage lymphoid cells. This previously unknown role of SYK as a cell cycle checkpoint regulator represents an unforeseen and significant challenge for inhibitors of SYK ATP binding site.