Transmodulation between phospholipase D and c-Src enhances cell proliferation.
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.
Ahn
Bong-Hyun
BH
Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Kim
Shi Yeon
SY
Kim
Eun Hee
EH
Choi
Kyeong Sook
KS
Kwon
Taeg Kyu
TK
Lee
Young Han
YH
Chang
Jong-Soo
JS
Kim
Myung-Suk
MS
Jo
Yang-Hyeok
YH
Min
Do Sik
DS
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
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