Regulation of Ack-Family Nonreceptor Tyrosine Kinases

Ack family non-receptor tyrosine kinases are unique with regard to their domain composition and regulatory properties. Human Ack1 (activated Cdc42-associated kinase) is ubiquitously expressed and is activated by signals that include growth factors and integrin-mediated cell adhesion. Stimulation leads to Ack1 autophosphorylation and to phosphorylation of additional residues in the C-terminus. The N-terminal SAM domain is required for full activation. Ack1 exerts some of its effects via protein-protein interactions that are independent of its kinase activity. In the basal state, Ack1 activity is suppressed by an intramolecular interaction between the catalytic domain and the C-terminal region. Inappropriate Ack1 activation and signaling has been implicated in the development, progression, and metastasis of several forms of cancer. Thus, there is increasing interest in Ack1 as a drug target, and studies of the regulatory properties of the enzyme may reveal features that can be exploited in inhibitor design

Regulation of Src and Csk nonreceptor tyrosine kinases in the filasterean Ministeria vibrans

ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.The development of the phosphotyrosine-based signaling system predated the evolution of multicellular animals. Single-celled choanoflagellates, the closest living relatives to metazoans, possess numerous tyrosine kinases, including Src family nonreceptor tyrosine kinases. Choanoflagellates also have Csk (C-terminal Src kinase), the enzyme that regulates Src in metazoans; however, choanoflagellate Csk kinases fail to repress the cognate Src. Here, we have cloned and characterized Src and Csk kinases from Ministeria vibrans, a filasterean (the sister group to metazoans and choanoflagellates). The two Src kinases (MvSrc1 and MvSrc2) are enzymatically active Src kinases, although they have low activity toward mammalian cellular proteins. Unexpectedly, MvSrc2 has significant Ser/Thr kinase activity. The Csk homologue (MvCsk) is enzymatically inactive and fails to repress MvSrc activity. We suggest that the low activity of MvCsk is due to sequences in the SH2-kinase interface, and we show that a point mutation in this region partially restores MvCsk activity. The inactivity of filasterean Csk kinases is consistent with a model in which the stringent regulation of Src family kinases arose more recently in evolution, after the split between choanoflagellates and multicellular animals. © 2014 American Chemical Society.Peer Reviewe

Regulation of Ack1 localization and activity by the amino-terminal SAM domain

<p>Abstract</p> <p>Background</p> <p>The mechanisms that regulate the activity of the nonreceptor tyrosine kinase Ack1 (activated Cdc42-associated kinase) are poorly understood. The amino-terminal region of Ack1 is predicted to contain a sterile alpha motif (SAM) domain. SAM domains share a common fold and mediate protein-protein interactions in a wide variety of proteins. Here, we addressed the importance of the Ack1 SAM domain in kinase activity.</p> <p>Results</p> <p>We used immunofluorescence and Western blotting to show that Ack1 deletion mutants lacking the N-terminus displayed significantly reduced autophosphorylation in cells. A minimal construct comprising the N-terminus and kinase domain (NKD) was autophosphorylated, while the kinase domain alone (KD) was not. When expressed in mammalian cells, NKD localized to the plasma membrane, while KD showed a more diffuse cytosolic localization. Co-immunoprecipitation experiments showed a stronger interaction between full length Ack1 and NKD than between full length Ack1 and KD, indicating that the N-terminus was important for Ack1 dimerization. Increasing the local concentration of purified Ack1 kinase domain at the surface of lipid vesicles stimulated autophosphorylation and catalytic activity, consistent with a requirement for dimerization and trans-phosphorylation for activity.</p> <p>Conclusions</p> <p>Collectively, the data suggest that the N-terminus of Ack1 promotes membrane localization and dimerization to allow for autophosphorylation.</p

ASTRO Journals' Data Sharing Policy and Recommended Best Practices.

Transparency, openness, and reproducibility are important characteristics in scientific publishing. Although many researchers embrace these characteristics, data sharing has yet to become common practice. Nevertheless, data sharing is becoming an increasingly important topic among societies, publishers, researchers, patient advocates, and funders, especially as it pertains to data from clinical trials. In response, ASTRO developed a data policy and guide to best practices for authors submitting to its journals. ASTRO's data sharing policy is that authors should indicate, in data availability statements, if the data are being shared and if so, how the data may be accessed

Database management and analysis of fisheries in Illinois: Final report, 1 March 1999-28 February 2002

Issued May 2002; F-69-RReport issued on: May 200

Canadian and U.S. Antitrust Law--Areas of Overlap between Anitrust and Import Relief Laws

Competition and Dispute Resolution in the North American Context and antitrust and free trade zone

A Demographic Approach to Race and Ethnicity in Metropolitan and Non-Metropolitan Regions of Arkansas, 1990 and 1999

This manuscript provides an empirical portrait of emergent trends in the growth, distribution, and racial and ethnic composition of Arkansas’ resident population. Particular attention is given to variation in the racial and ethnic composition of the estimated population among different regions of the state. During the 1990’s, racial and ethnic diversity increased statewide due in large part to Hispanic population growth in all regions. Black population growth was greatest in central Arkansas while Asian and Native American population growth increased most rapidly in the northwest metropolitan regions of the state. Overall, both metropolitan and non-metropolitan Arkansas communities have a more diverse mix of ethnic populations than has been known in the past

Diets of and trophic relationships among dominant marine nekton within the northern California Current ecosystem

In this study we analyzed the diets of 26 nekton species collected from two years (2000 and 2002) off Oregon and northern California to describe dominant nekton trophic groups of the northern California Current (NCC) pelagic ecosystem. We also examined interannual variation in the diets of three nekton species. Cluster analysis of predator diets resulted in nekton trophic groups based on the consumption of copepods, euphausiids, brachyuran larvae, larval juvenile fishes, and adult nekton. However, many fish within trophic groups consumed prey from multiple trophic levels—euphausiids being the most widely consumed. Comparison of diets between years showed that most variation occurred with changes in the contribution of euphausiids and brachyuran larvae to nekton diets. The importance of euphausiids and other crustacean prey to nekton indicates that omnivory is an important characteristic of the NCC food web; however it may change during periods of lower or higher upwelling and ecosystem production

Juvenile salmonid distribution, growth, condition, origin, and environmental and species associations in the Northern California Current

Information is summarized on juvenile salmonid distribution, size, condition, growth, stock origin, and species and environmental associations from June and August 2000 GLOBEC cruises with particular emphasis on differences related to the regions north and south of Cape Blanco off Southern Oregon. Juvenile salmon were more abundant during the August cruise as compared to the June cruise and were mainly distributed northward from Cape Blanco. There were distinct differences in distribution patterns between salmon species: chinook salmon were found close inshore in cooler water all along the coast and coho salmon were rarely found south of Cape Blanco. Distance offshore and temperature were the dominant explanatory variables related to coho and chinook salmon distribution. The nekton assemblages differed significantly between cruises. The June cruise was dominated by juvenile rockfishes, rex sole, and sablefish, which were almost completely absent in August. The forage fish community during June comprised Pacific herring and whitebait smelt north of Cape Blanco and surf smelt south of Cape Blanco. The fish community in August was dominated by Pacific sardines and highly migratory pelagic species. Estimated growth rates of juvenile coho salmon were higher in the GLOBEC study area than in areas farther north. An unusually high percentage of coho salmon in the study area were precocious males. Significant differences in growth and condition of juvenile coho salmon indicated different oceanographic environments north and south of Cape Blanco. The condition index was higher in juvenile coho salmon to the north but no significant differences were found for yearling chinook salmon. Genetic mixed stock analysis indicated that during June, most of the Chinook salmon in our sample originated from rivers along the central coast of Oregon. In August, chinook salmon sampled south of Cape Blanco were largely from southern Oregon and northern California; whereas most chinook salmon north of Cape Blanco were from the Central Valley in California