RASERK signaling can be initiated by tyrosine kinase receptors that activate RAS, followed by the RAFMEK ERK kinase cascade, resulting in phosphorylated ERK. pERK, in turn, phosphorylates transcription fac tors, including some members of the ETS family, leading to increased selleck catalog transcriptional activation of target genes. PI3K phosphorylates phosphoinositides leading to activation of downstream proteins such as the kinase AKT. PTEN, a phosphatase, can reverse this process and acts as a tumor suppressor. Activated AKT has mul tiple functions, one being the activation of the mTOR containing signaling complex mTORC1, which alters translational control of gene expression. AKT also acti vates the mTORC2 complex, which provides positive feedback by phosphorylating and activating AKT.

The RASERK and PI3KAKT Inhibitors,Modulators,Libraries pathways are highly intercon nected. For example, RAS can activate PI3K, and AKT can phosphorylate and inhibit RAF. A rearrangement of chromosome 21 that results in fu sion of the TMPRSS2 and ERG genes occurs in approxi mately 50% of prostate tumors. TMPRSS2 ERG joins the 5 regulatory regions and 5 UTR of TMPRSS2, which is highly expressed in prostate, to the open read ing Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries frame of ERG, resulting in expression of either a full length, or N terminally truncated version of ERG, an ETS family transcription factor that is not normally expressed in prostate cells. Similar fusions that over express the ETS genes ETV1, ETV4, Inhibitors,Modulators,Libraries and ETV5 occur in another 10% of prostate tumors. Expression of these oncogenic ETS family members in prostate cells drives cellular invasion and migration and pro motes the transition from neoplasia to carcinoma.

We previously reported that over expression of ERG or ETV1 can activate a gene expression program that drives cell migration. Genes in this program are regulated by a RAS responsive enhancer sequence consisting of neighboring ETS and AP Inhibitors,Modulators,Libraries 1 transcription factor binding sites. In normal prostate cells, these genes can be activated by RASERK signaling, likely via ERK phosphorylation of an ETS protein bound this to the ETSAP 1 sequence. There are 12 15 ETS transcription factors expressed in normal prostate that are candidates for this role. Our previ ous data support a model that when ERG, ETV1, ETV4, or ETV5 are over expressed in prostate cells, they can re place the ETS family member normally bound to ETS AP 1 sites and activate the RAS inducible cell migration gene expression program in the absence of RASERK signaling. Thus over expression of one of these four oncogenic ETS genes can mimic RASERK path way activation. The two most common genomic aberrations in prostate cancer are PTEN deletion and the TMPRSS2ERG re arrangement.