Novel type of signaling molecules: Protein kinases covalently linked with ion channels

Recently we identified a new class of protein kinases with a novel type of catalytic domain structurally and evolutionarily unrelated to the conventio nal eukaryotic protein kinases. This new class, which we named alpha-kinase s, is represented by eukaryotic elongation factor-2 kinase and the Dictyost elium myosin heavy chain kinases. Here we cloned, sequenced, and analyzed t he tissue distribution of live new putative mam malian alpha -kinases: mela noma alpha -kinase, kidney alpha -kinase, heart alpha -kinase, skeletal mus cle alpha -kinase, and lymphocyte alpha -kinase. All five are large protein s of more than 1000 amino acids with an alpha -kinase catalytic domain loca ted in the carboxyterminal part. We expressed the catalytic domain of melan oma alpha -kinase in Escherichia coli, and found that it autophosphorylates at threonine residues, demonstrating that it is a genuine protein kinase. Unexpectedly, we found that long aminoterminal portions of melanoma and kid ney alpha -kinases represent new members of the TRP ion channel Family, whi ch are thought to mediate the capacitative Ca2+ Entry in nonexcitable mamma lian cells. This suggests that melanoma and kidney alpha -kinases, which re present a novel type of signaling molecule, art: involved in the regulation of Ca2+ influx in mammalian cells.