Connexins: a myriad of functions extending beyond assembly of gap junction channels

Connexins constitute a large family of trans-membrane proteins that allow intercellular communication and the transfer of ions and small signaling molecules between cells. Recent studies have revealed complex translational and post-translational mechanisms that regulate connexin synthesis, maturation, membrane transport and degradation that in turn modulate gap junction intercellular communication. With the growing myriad of connexin interacting proteins, including cytoskeletal elements, junctional proteins, and enzymes, gap junctions are now perceived, not only as channels between neighboring cells, but as signaling complexes that regulate cell function and transformation. Connexins have also been shown to form functional hemichannels and have roles altogether independent of channel functions, where they exert their effects on proliferation and other aspects of life and death of the cell through mostly-undefined mechanisms. This review provides an updated overview of current knowledge of connexins and their interacting proteins, and it describes connexin modulation in disease and tumorigenesis

Characterization of a tumor-associated activating mutation of the p110β PI 3-kinase.

The PI3-kinase pathway is commonly activated in tumors, most often by loss of PTEN lipid phosphatase activity or the amplification or mutation of p110α. Oncogenic mutants have commonly been found in p110α, but rarely in any of the other catalytic subunits of class I PI3-kinases. We here characterize a p110β helical domain mutation, E633K, first identified in a Her2-positive breast cancer. The mutation increases basal p110β activity, but does not affect activation of p85/p110β dimers by phosphopeptides or Gβγ. Expression of the mutant causes increases in Akt and S6K1 activation, transformation, chemotaxis, proliferation and survival in low serum. E633 is conserved among class I PI3 Ks, and its mutation in p110β is also activating. Interestingly, the E633K mutant occurs near a region that interacts with membranes in activated PI 3-kinases, and its mutation abrogates the requirement for an intact Ras-binding domain in p110β-mediated transformation. We propose that the E633K mutant activates p110β by enhancing its basal association with membranes. This study presents the first analysis of an activating oncogenic mutation of p110β

Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK

Significance With no lysine (K) (WNK)1, which is mutated in pseudohypoaldosteronism type II (PHAII) autosomal dominant hypertension, is a large, complex enzyme essential for development, blood pressure control, and many cellular functions. WNK1 signaling is largely mediated by two downstream protein kinases, OSR1 (oxidative stress responsive 1) and SPAK (STE20/SPS1-related proline-, alanine-rich kinase), sometimes considered redundant in terms of WNK1 function. This study characterizes an essential contribution of WNK1 in angiogenesis and presents a mechanism of clear bifurcation in WNK1-dependent functions between OSR1 and SPAK, with SPAK regulating WNK1 effects on proliferation and OSR1 mediating effects on invasion. Our work also identifies a previously unidentified link between WNK1 and the zinc-finger transcription factor Slug, with implications in cancer biology. This study also suggests potential mechanisms for cardiovascular defects associated with PHAII.</jats:p