scholarly journals Different inhibitory effect of imatinib on phosphorylation of mitogen-activated protein kinase and Akt and on proliferation in cells expressing different types of mutant platelet-derived growth factor receptor-?

2004 ◽  
Vol 111 (3) ◽  
pp. 317-321 ◽  
Author(s):  
Akiko Ohashi ◽  
Kazuo Kinoshita ◽  
Koji Isozaki ◽  
Toshirou Nishida ◽  
Yasuhisa Shinomura ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Growth Factor Receptor ◽  
Inhibitory Effect ◽  
Mitogen Activated Protein Kinase ◽  
Platelet Derived Growth Factor ◽  
Different Types ◽  
Mitogen Activated Protein ◽  
In Cells

scholarly journals Dok-1 Independently Attenuates Ras/Mitogen-Activated Protein Kinase and Src/c-Myc Pathways To Inhibit Platelet-Derived Growth Factor-Induced Mitogenesis

2006 ◽  
Vol 26 (7) ◽  
pp. 2479-2489 ◽  
Author(s):  
Mingming Zhao ◽  
Justyna A. Janas ◽  
Masaru Niki ◽  
Pier Paolo Pandolfi ◽  
Linda Van Aelst
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Adaptor Proteins ◽  
Inhibitory Effect ◽  
Mitogen Activated Protein Kinase ◽  
Platelet Derived Growth Factor ◽  
Mapk Activation ◽  
Interacting Protein ◽  
Mitogen Activated Protein

ABSTRACT The Dok adaptor proteins play key regulatory roles in receptor and non-receptor kinase-initiated signaling pathways. Dok-1, the prototype member of this family, negatively regulates cell proliferation elicited by numerous growth factors, including platelet-derived growth factor (PDGF). However, how Dok-1 exerts its negative effect on mitogenesis has remained elusive. Using Dok-1 knockout cells and Dok-1 mutants deficient in binding to specific Dok-1-interacting proteins, we show that Dok-1 interferes with PDGF-stimulated c-myc induction and Ras/mitogen-activated protein kinase (MAPK) activation by tethering different signaling components to the cell membrane. Specifically, Dok-1 attenuates PDGF-elicited c-myc induction by recruiting Csk to active Src kinases, whereupon their activities and consequent c-myc induction are diminished. On the other hand, Dok-1 negatively regulates PDGF-induced MAPK activation by acting on Ras-GAP and at least one other Dok-1-interacting protein. Importantly, we demonstrate that Dok-1's actions on both of these signaling pathways contribute to its inhibitory effect on mitogenesis. Our data suggest a mechanistic basis for the inhibitory effect of Dok-1 on growth factor-induced mitogenesis and its role as a tumor suppressor.

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