TAT-1, a phosphatidylserine flippase, affects molting and regulates membrane trafficking in the epidermis of C. elegans.

Membrane trafficking is a conserved process required for import, export, movement, and distribution of proteins and other macromolecules within cells. The Caenorhabditis elegans NIMA-related kinases NEKL-2 (human NEK8/9) and NEKL-3 (human NEK6/7) are conserved regulators of membrane trafficking and are required for the completion of molting. Using a genetic approach we identified reduction-of-function mutations in tat-1 that suppress nekl-associated molting defects.

TAT-1, a phosphatidylserine flippase, affects molting and regulates membrane trafficking in the epidermis of .

Unlabelled: Membrane trafficking is a conserved process required for the movement and distribution of proteins and other macromolecules within cells. The NIMA-related kinases NEKL-2 (human NEK8/9) and NEKL-3 (human NEK6/7) are conserved regulators of membrane trafficking and are required for the completion of molting. We used a genetic approach to identify reduction-of-function mutations in that suppress -associated molting defects.

A conserved protein tyrosine phosphatase, PTPN-22, functions in diverse developmental processes in C. elegans.

Protein tyrosine phosphatases non-receptor type (PTPNs) have been studied extensively in the context of the adaptive immune system; however, their roles beyond immunoregulation are less well explored. Here we identify novel functions for the conserved C. elegans phosphatase PTPN-22, establishing its role in nematode molting, cell adhesion, and cytoskeletal regulation.

A conserved protein tyrosine phosphatase, PTPN-22, functions in diverse developmental processes in .

Protein tyrosine phosphatases non-receptor type (PTPNs) have been studied extensively in the context of the adaptive immune system; however, their roles beyond immunoregulation are less well explored. Here we identify novel functions for the conserved phosphatase PTPN-22, establishing its role in nematode molting, cell adhesion, and cytoskeletal regulation. Through a non-biased genetic screen, we found that loss of PTPN-22 phosphatase activity suppressed molting defects caused by loss-of-function mutations in the conserved NIMA-related kinases NEKL-2 (human NEK8/NEK9) and NEKL-3 (human NEK6/NEK7), which act at the interface of membrane trafficking and actin regulation.

A quantitative analysis of kinase inhibitor selectivity.

Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome.

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases.

To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved "gatekeeper" threonine residue near the kinase active site.

A small molecule-kinase interaction map for clinical kinase inhibitors.

Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases.

Drosophila retained/dead ringer is necessary for neuronal pathfinding, female receptivity and repression of fruitless independent male courtship behaviors.

Mutations in the Drosophila retained/dead ringer (retn) gene lead to female behavioral defects and alter a limited set of neurons in the CNS. retn is implicated as a major repressor of male courtship behavior in the absence of the fruitless (fru) male protein. retn females show fru-independent male-like courtship of males and females, and are highly resistant to courtship by males.

blue cheese mutations define a novel, conserved gene involved in progressive neural degeneration.

A common feature of many human neurodegenerative diseases is the accumulation of insoluble ubiquitin-containing protein aggregates in the CNS. Although Drosophila has been helpful in understanding several human neurodegenerative disorders, a loss-of-function mutation has not been identified that leads to insoluble CNS protein aggregates. The study of Drosophila mutations may identify unique components that are associated with human degenerative diseases.

DSF nuclear receptor acts as a repressor in culture and in vivo.

Loss-of-function mutations affecting the dissatisfaction (DSF) nuclear receptor alter both sexual behavior and the sex-specific nervous system in Drosophila. As a step toward understanding the way DSF controls development and function of the nervous system, we have analyzed the regulatory activities of the DSF protein. DSF prefers an atypical DNA half site, AAGTCA.