oncogenic kinases in human cancers

oncogenic kinases in human cancers
Druillennec Sabine, Dorard Coralie, Eychene Alain "Journal of nucleic acids"
Among the 518 protein kinases encoded from the human kinome, numerous of them act as oncoproteins in human cancers. Like other eukaryotic genes, oncogenes encoding protein kinases are frequently subjected to option splicing in coding as well as noncoding sequences.
Inside the present paper, we will illustrate how option splicing can considerably effect on the physiological features of oncogenic protein kinases, as demonstrated by mouse genetic product studies. This consists of examples of membrane-bound tyrosine kinases receptors (FGFR2, Ret, TrkB, ErbB4, and VEGFR) together with cytosolic protein kinases (b-raf inhibitor).
We'll additional talk about how regular alternative splicing occasions of those kinases are in a few cases implicated in oncogenic processes in the course of tumor progression (FGFR, TrkB, ErbB2, Abl, and AuroraA). Lastly, we will current typical examples of aberrant splicing responsible for that deregulation of oncogenic kinases activity in cancers (AuroraB, Jak2, Kit, Met, and Ron).
Cellular transformation induced by oncogenic tyrosine kinases can be a multistep approach involving activation of growth-promoting signaling pathways and inactivation of suppressor molecules. Dok-1 is an adaptor protein that acts as being a negative regulator of tyrosine kinase-initiated signaling and opposes oncogenic tyrosine kinase-mediated cell transformation.
Findings that its reduction facilitates transformation induced by oncogenic tyrosine kinases recommend that Dok-1 inactivation could constitute an intermediate action in oncogenesis pushed by these oncoproteins. Nonetheless, whether or not Dok-1 is topic to regulation by oncogenic tyrosine kinases remained unidentified.
In this study, we show that oncogenic tyrosine kinases, which includes p210(bcr-abl) and oncogenic types of Src, downregulate Dok-1 by targeting it for degradation via the ubiquitin-proteasome pathway. This method is dependent on the tyrosine kinase activity in the oncoproteins and it is mediated mainly by lysine-dependent polyubiquitination of Dok-1.
Importantly, restoration of Dok-1 levels strongly suppresses transformation of cells expressing oncogenic tyrosine kinases, and this suppression is much more pronounced in the context of the Dok-1 mutant which is mostly refractory to oncogenic tyrosine kinase-induced degradation. Our findings recommend that proteasome-mediated downregulation of Dok-1 can be a important mechanism by which oncogenic tyrosine kinase inhibitors conquer the inhibitory impact of Dok-1 on cellular transformation and tumor progression.