Sphingosine kinases signalling in carcinogenesis.
Sphingosine kinases (Sphk1 and 2) regulate the prodution of sphingosine-1-phosphate (S1P), that is key molecule in cancer development. SphK1, which is commonly overexpressed in malignant tumours, significantly contributes to the pathogenesis of various types of cancer as well as to resistance to different Tyrosine Kinase inibitors (TKIs). Even, SphK2 may promote apoptosis and inhibit cell growth but its role has not yet been fully understood in pathologic conditions. Different growth factorsinduced activation of receptor tyrosine kinases (RTKs) results in production of Sphk1 which catalyzes the phosphorylation of sphingosine. Such enzyme, in turn, is involved in many cellular processes by its five receptors. These are able to transactivate RTKs through amplification of a positive-feedback signaling loop. In conclusion, development of pharmacological inhibitors of SphK1 has been limited by the lack of completely understanding of the enzymatic activation mechanisms of SphK1.
Gabriella
G
Marfe
Giovanna
G
Mirone
Arvind
A
Shukla
Department of Biochemistry and Biophysics, Second University of Naples, Via De Crecchio 7, Naples 80138, Italy. gabmarfe@alice.it.
Carla
C
Di Stefano
D000818:Animals; D063646:Carcinogenesis; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism; D000099157:Sphingosine Kinase
D017853:Phosphotransferases (Alcohol Group Acceptor); D013107:Sphingolipids; D000099157:Sphingosine Kinase