Requirement of multiple signaling pathways for the augmented production of hyaluronan by v-Src.
Malignant transformation of cells is frequently associated with an augmented production of hyaluronan and the subsequent formation of a hyaluronan-matrix. In v-Src-transformed cells, hyaluronan directly activate cell motility in a tumor-specific manner. Despite its importance, the mechanism by which v-Src activates hyaluronan production remains unclear. Here we report that multiple signaling pathways are required for the augmented production of hyaluronan. Either the expression of a dominant negative Ras or the treatment of cells with manumycin A, a Ras farnesyltransferase inhibitor, was able to suppress hyaluronan production. In contrast, expression of MEK1EE, a constitutive form of MEK1, activated both hyaluronan synthase expression and hyaluronan production. AG-490, a Jak-2 inhibitor, or LY294002, a PI3K inhibitor, similarly suppressed the augmented production of hyarulonan. Taken together, our results suggest the involvement of multiple signaling pathways, including Ras-dependent and independent ones, in augmented hyaluronan production by v-Src.
Naito
Yuko
Y
Division of Cancer Biology, Nagoya University School of Medicine, Showaku, Nagoya 466-8550, Japan.
Suzuki
Noriko
N
Huang
Pengyu
P
Hasegawa
Hitoki
H
Sohara
Yasuyoshi
Y
Iwamoto
Takashi
T
Hamaguchi
Michinari
M
D000818:Animals; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D015151:Immunoblotting; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics* / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology
D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007527:Isoenzymes; D009025:Morpholines; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases; D053614:Janus Kinase 2; D015688:Oncogene Protein pp60(v-src); D048369:MAP Kinase Kinase 1; C054474:manumycin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D004121:Dimethyl Sulfoxide