title: Transmodulation between phospholipase D and c-Src enhances cell proliferation.
abstract: Phospholipase D (PLD) has been implicated in the signal transduction pathways initiated by several mitogenic protein tyrosine kinases. We demonstrate for the first time that most notably PLD2 and to a lesser extent the PLD1 isoform are tyrosine phosphorylated by c-Src tyrosine kinase via direct association. Moreover, epidermal growth factor induced tyrosine phosphorylation of PLD2 and its interaction with c-Src in A431 cells. Interaction between these proteins is via the pleckstrin homology domain of PLD2 and the catalytic domain of c-Src. Coexpression of PLD1 or PLD2 with c-Src synergistically enhances cellular proliferation compared with expression of either molecule. While PLD activity as a lipid-hydrolyzing enzyme is not affected by c-Src, wild-type PLDs but not catalytically inactive PLD mutants significantly increase c-Src kinase activity, up-regulating c-Src-mediated paxillin phosphorylation and extracellular signal-regulated kinase activity. These results demonstrate the critical role of PLD catalytic activity in the stimulation of Src signaling. In conclusion, we provide the first evidence that c-Src acts as a kinase of PLD and PLD acts as an activator of c-Src. This transmodulation between c-Src and PLD may contribute to the promotion of cellular proliferation via amplification of mitogenic signaling pathways.
authors.affiliation: Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Bong-Hyun
authors.initials: BH
authors.lastname: Ahn
authors.forename: Shi Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Kim
authors.forename: Kyeong Sook
authors.initials: KS
authors.lastname: Choi
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Jong-Soo
authors.initials: JS
authors.lastname: Chang
authors.forename: Myung-Suk
authors.initials: MS
authors.lastname: Kim
authors.forename: Yang-Hyeok
authors.initials: YH
authors.lastname: Jo
authors.forename: Do Sik
authors.initials: DS
authors.lastname: Min
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D020134:Catalytic Domain; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D051419:Paxillin; D010739:Phospholipase D / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases
chemical_list: D003598:Cytoskeletal Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; C496062:Pxn protein, mouse; C496063:Pxn protein, rat; D014443:Tyrosine; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D020928:Mitogen-Activated Protein Kinases; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1