Sphingomyelin-derived lipids differentially regulate the extracellular signal-regulated kinase 2 (ERK-2) and c-Jun N-terminal kinase (JNK) signal cascades in airway smooth muscle.
In ASM cells platelet-derived growth factor stimulates rapid transient sphingosine phosphate formation, the activation of extracellular signal-regulated kinase 2 (ERK-2), the phosphorylation of p70(56K), and a ninefold increase in DNA synthesis. In contrast, this growth factor fails to activate c-Jun N-terminal kinase (JNK). Based upon these findings, we have tested whether the sphingomyelin-derived sphingolipids play a role in growth factor signalling by assessing their effect on ERK-2, JNK, and p70(56K). We demonstrate that sphingosine phosphate induces the activation of ERK-2, is ineffective against JNK, and fails to induce the phosphorylation of p70(56K). The latter may explain why it is a poor mitogen when added directly to ASM cells. In contrast, sphingosine and cell-permeable ceramides elicit the prominent tyrosyl phosphorylation and activation of JNK, are poor stimulators of ERK-2, and do not induce the phosphorylation of p70(56K). Therefore, the specificity of signalling through either ERK-2 or JNK cascades may be determined by the rapid agonist-dependent interconversion of these sphingomyelin-derived lipids. This may also provide a dynamic mechanism that enables growth factors and cytokines to elicit pleiotropic cell responses, such as proliferation and cell survival. For instance, both ceramide and sphingosine will elicit growth arrest via activation of JNK, whereas sphingosine phosphate will potentiate growth-factor-stimulated DNA synthesis, a consequence of the activation of ERK-2, Furthermore, under certain conditions, sphingosine and ceramide stimulate cAMP formation, a negative modulator of cell growth, whereas sphingosine phosphate depresses cAMP, thereby enhancing its own growth-promoting properties. From these studies, it is evident that sphingosine phosphate displays a signalling profile that is consistent with it mediating part of the action of platelet-derived growth factor.
Pyne
S
S
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland.
Chapman
J
J
Steele
L
L
Pyne
N J
NJ
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D006168:Guinea Pigs; D048031:JNK Mitogen-Activated Protein Kinases; D008246:Lysophospholipids; D048670:MAP Kinase Kinase 4; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012132:Respiratory Muscles / Q000187:drug effects / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism / Q000494:pharmacology; D013109:Sphingomyelins / Q000378:metabolism* / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
D002518:Ceramides; D008246:Lysophospholipids; D010982:Platelet-Derived Growth Factor; D013107:Sphingolipids; D013109:Sphingomyelins; C060506:sphingosine 1-phosphate; D004247:DNA; D000242:Cyclic AMP; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D010739:Phospholipase D; D013110:Sphingosine