Similar findings were reported for many breast cancer cell lines where RET expression corre lated strongly with ERa expression and or ErbB2 HER2 overexpression. RET is a receptor tyrosine kinase protein of 150 kDa that is expressed and required during early development for the formation of neural crest derived lineages, kidney organogenesis, and spermatogenesis. Crizotinib RET is consid ered the driving oncogene in various neoplasms of the thyroid, where specific mutations lead to defined tumor types. The RET protein spans the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This positioning of the protein allows it to interact with specific factors outside the cell and to receive signals that help the cell respond to its environment.

Inhibitors,Modulators,Libraries When molecules that stimulate growth and development such as growth factors attach to the RET protein, a complex cascade of chemical reactions inside the cell is triggered. These reac Inhibitors,Modulators,Libraries tions instruct the cell to undergo certain changes, such as dividing or maturing to take on specialized functions. RET is the receptor for a family of glial derived neurotrophic factor ligands, which includes GDNF, artemin, neurturin, and persephin. These ligands bind RET in conjunction with glycosylphosphatidylinositol anchored co receptors of the GDNF receptor alpha family, and the ligand co receptor RET complex formation results in transient RET dimerization and activation of the RET tyr osine kinase domain.

RET protein dimerization results in autophosphorylation of several intracellular RET Inhibitors,Modulators,Libraries tyrosine residues, and these autophosphorylation sites serve as binding sites for a variety of docking proteins. In particu lar, the tyrosine Y1062 has been shown to bind Src homol ogy and collagen, insulin receptor substrate1 2, fibroblast growth factor receptor Inhibitors,Modulators,Libraries substrate 2, and protein kinase C alpha. These proteins are able to activate multiple signal ing pathways, including MAPK, PI3K AKT, RAS extracel lular signal regulated kinase and Rac c jun NH kinase, which are mediators of cell motility, proliferation, differen tiation, and survival. While our present study indi cates that PEDF is capable of suppressing RET signaling in endocrine resistant cells, we do not know the exact mechanism by which this occurs.

We should note Inhibitors,Modulators,Libraries that RET is the receptor for several ligands including GNDF, which is a potent neurotropic factor similar to PEDF. Like other trophic factors, PEDF is thought to exert its biologi cal effects by specifically www.selleckchem.com/products/carfilzomib-pr-171.html binding and activating one or more receptors. While PEDF receptors have not yet been fully characterized, there is a possibility that PEDF, like GDNF, is able to bind to RET and thus regulate its expres sion and activity in breast cancer cells. This possibility is currently being investigated in our laboratory.