Dasatinib inhibits the development of metastases in a mouse model of pancreatic ductal adenocarcinoma.

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive and metastatic disease for which conventional treatments are of limited efficacy. A number of agents in development are potential anti-invasive and antimetastatic agents, including the Src kinase inhibitor dasatinib. The aim of this study was to assess the importance of Src in human PDAC and to use a genetically engineered mouse model of PDAC to determine the effects of dasatinib on PDAC progression.

Identification of the insulin-responsive tyrosine phosphorylation sites on IRSp53.

The 53-kDa insulin receptor substrate protein (IRSp53) is part of a regulatory network that organises the actin cytoskeleton in response to stimulation by small GTPases, promoting formation of actin-rich cell protrusions such as filopodia and lamellipodia. It had been established earlier that IRSp53 is tyrosine phosphorylated in response to stimulation of the insulin and insulin-related growth factor receptors, but the consequences of tyrosine phosphorylation for IRSp53 function are unknown. Here, we have used a variety of IRSp53 truncation and point mutants to identify insulin-responsive tyrosine phosphorylation sites on IRSp53.

Glial cell line-derived neurotrophic factor protects astrocytes from staurosporine- and ischemia- induced apoptosis.

Glial cell line-derived neurotrophic factor (GDNF) promotes the survival and functions of neurons. It has been shown to be a promising candidate in the treatment of ischemia and other neurodegenerative diseases. We transfected mouse astrocytes in primary cultures with a human GDNF gene and found that their conditioned medium could not only support the growth and survival of cultured dopaminergic neurons but also protect astrocytes from staurosporine- and ischemia-induced apoptosis.

Structural basis of filopodia formation induced by the IRSp53/MIM homology domain of human IRSp53.

The scaffolding protein insulin receptor tyrosine kinase substrate p53 (IRSp53), a ubiquitous regulator of the actin cytoskeleton, mediates filopodia formation under the control of Rho-family GTPases. IRSp53 comprises a central SH3 domain, which binds to proline-rich regions of a wide range of actin regulators, and a conserved N-terminal IRSp53/MIM homology domain (IMD) that harbours F-actin-bundling activity. Here, we present the crystal structure of this novel actin-bundling domain revealing a coiled-coil domain that self-associates into a 180 A-long zeppelin-shaped dimer.