title: Substrate-specific modulation of Src-mediated phosphorylation of Ras and caseins by sphingosines and other substrate modulators.
abstract: It is important for the understanding of protein kinase action to differentiate between regulation at the enzyme and at the substrate levels. For example, the inhibitors dinitrophenol-tyrosine and tyrphostins act at the enzyme level to inhibit phosphorylation of all substrates by c-Src and v-Src kinases. In contrast, polylysine acts at the substrate level to stimulate Src-mediated phosphorylation of beta-casein but to inhibit phosphorylation of alpha-casein. Here we demonstrate novel enzyme-specific and substrate-specific modulations of Src kinase activity of potential physiological significance. At the enzyme level, we observed that c-Src kinase preferentially phosphorylates alpha-casein, while the v-Src kinase prefers beta-casein. At the substrate level we observed substrate-specific modulation by physiological factors including sphingosine, sphingosine derivatives and the ganglioside GM3. Galactosyl-sphingosine (psychosine) was more effective in stimulating phosphorylation of beta-casein and poly(E1A1Y1) than sphingosine. Glucosyl- and lactosyl-sphingosine were ineffective. Rat was extensively phosphorylated by c-Src in the presence of polylysine, and to a lesser extent in the sphingosine and galactosyl-sphingosine. These unexpected differences point out another potential mechanism for regulation of c-Src and v-Src kinase activities and may help to explain some of the pleotyptic manifestations of protein tyrosine kinase actions.
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002364:Caseins / Q000378:metabolism*; D002417:Cattle; D004285:Dogs; D011905:Genes, ras; D016391:Genes, src; D006801:Humans; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D013110:Sphingosine / Q000494:pharmacology*; D013379:Substrate Specificity; D019061:src-Family Kinases
chemical_list: D002364:Caseins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D015688:Oncogene Protein pp60(v-src); D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; C000631346:CSK protein, human; D013110:Sphingosine