54 research outputs found
Receptor Tyrosine Kinases as Therapeutic Targets in Rhabdomyosarcoma
Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas of childhood and adolescence. To date, there are no effective treatments that target the genetic abnormalities in RMS, and current treatment options for high-risk groups are not adequate. Over the past two decades, research into the molecular mechanisms of RMS has identified key genes and signaling pathways involved in disease pathogenesis. In these studies, members of the receptor tyrosine kinase (RTK) family of cell surface receptors have been characterized as druggable targets for RMS. Through small molecule inhibitors, ligand-neutralizing agents, and monoclonal receptor-blocking antibodies, RTK activity can be manipulated to block oncogenic properties associated with RMS. Herein, we review the members of the RTK family that are implicated in RMS tumorigenesis and discuss both the problems and promise of targeting RTKs in RMS
Cerebral Cavernous Malformation 2 Protein Promotes Smad Ubiquitin Regulatory Factor 1-mediated RhoA Degradation in Endothelial CellsS⃞
Mutation of CCM2 predisposes individuals to cerebral cavernous
malformations, vascular abnormalities that cause seizures and hemorrhagic
stroke. CCM2 has been proposed to regulate the activity of RhoA for
maintenance of vascular integrity. Herein, we define a novel mechanism where
the CCM2 phosphotyrosine binding (PTB) domain binds the ubiquitin ligase (E3)
Smurf1, controlling RhoA degradation. Brain endothelial cells with knockdown
of CCM2 have increased RhoA protein and display impaired directed cell
migration. CCM2 binding of Smurf1 increases Smurf1-mediated degradation of
RhoA. CCM2 does not significantly alter the catalytic activity of Smurf1, nor
is CCM2 a Smurf1 substrate. Rather the CCM2-Smurf1 interaction functions to
localize Smurf1 for RhoA degradation. These findings provide a molecular
mechanism for the pathogenesis of cerebral cavernous malformations (CCM)
resulting from loss of CCM2-mediated localization of Smurf1, which controls
RhoA degradation required for maintenance of normal endothelial cell
physiology
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